NL2000284C2 - Pyrazine derivatives. - Google Patents

Description

Pyrazine derivatives

This invention relates to pyrazine derivatives. More specifically, this invention relates to heteroaryl substituted N- [6-amino-5-aryl-5-pyrazin-2-yl] carboxamide derivatives and to processes for the preparation of such derivatives, to intermediates used in the preparation of such derivatives, on compositions containing such derivatives and on the uses of such derivatives.

The pyrazine derivatives of the present invention are sodium channel modulators and have a number of therapeutic uses, particularly in the treatment of pain. More particularly, the pyrazine derivatives of the invention are Navis modulators. Preferred pyrazine derivatives according to the invention exhibit an affinity for the Navis channel that is greater than its affinity for the tetrodotoxin-sensitive sodium channels (TTX-S). More preferred pyrazine derivatives according to the invention exhibit at least a 2-fold selectivity for the Navis channel compared to the tetrodotoxin-sensitive sodium channels, and most preferably an 8-fold selectivity.

The Navi 8 channel is a sodium channel with control voltage which is expressed in nociceptors, the sensory neurons that are responsible for transmitting pain stimuli. The rat channel and the human channel were cloned in 1996 and 1998, respectively (Nature 1996; 379: 257-262; Pain 1998 (Nov); 78 (2): 107-114). The Navi.s channel was previously known as SNS (sensory neuron specific) and PN3 (peripheral nerve type 3). The Navi.s channel is atypical in that it exhibits resistance to the blocking effects of the puffer-toxin tetrodotoxin and is believed to underlie the slow control voltage and tetrodotoxin-resistant (TTX-R) sodium currents recorded from dorsal root ganglion neurons. The closest related molecular familied of the Navi.s channel is the Navi.s channel, which is the sodium channel of the heart, with which it shares approximately 60% homology. The Navi.s channel is expressed to the highest degree in the "small cells" of the dorsal root ganglia (DRG). These are believed to be the C and A delta cells which are the putative polymodal nociceptors, or pain sensors. Under normal circumstances, the Navi-2000284 2 channel is not expressed anywhere else than in subpopulations of DRG neurons. The Navi.s channels are believed to contribute to the DRG sensitization process and also to hyperexcitability due to nerve injury. Inhibitory modulation of the Navis channels is aimed at reducing the excitability of nociceptors, by preventing them from contributing to the excitation process.

Studies have shown that Navi.g anesthesia leads to a blunted pain phenotype, primarily for inflammatory challenges (AN Akopian et al., Nat. Neurosci. 1999; 2; 541-548) and that Navi s reduction reduces pain behavior in this case neuropathic pain (J. lai et al., Pain, 2002 (Jan); 95 (1-2): 143-152). Coward et al. And Yiangou et al. Have shown that NaVu appears to be expressed in pain conditions (Pain. 2000 (March); 85 (1-2): 41-50 and FEBS Lett. 2000 (Feb 11) 467 (2-3): 249-252).

It has also been shown that the Navi.e channel is expressed in structures related to the back and dental pulp and there is evidence of a role in causalgia, gastric inflammation and multiple sclerosis (Bucknill et al., Spine. 2002 ( Jan 15), 27 (2): 135-140: Shembalker et al., Eur J Pain 2001, 5 (3): 319-323: Laird et al., J Neurosci 2002 (0ct 1); 22 (19) : 8352-8356: Black et al., Neuroreport 1999 (Apr 6); 10 (5): 913918 and Proc. Natl. Acad. Sci. USA 2000: 97: 11598-11602).

Various sodium channel modulators are known for use as anticonvulsants or antidepressants, such as carbamazepine, amitriptyline, lamotrigine and riluzole, all of which target tetradotoxin-sensitive (TTX-S) sodium channels in the brain. Such TTX-S agents suffer from dose-limiting side effects, including dizziness, ataxia and somnolence, mainly due to the effect on TTX-S channels in the brain.

In WO-A-03/051366, protein kinase inhibitors are discussed which are useful for the treatment of cancer. In WO-A-03/45924, CRFi antagonists are discussed which are useful for the treatment of disorders related to the CNS. In WO-A-98/38174 pyrazine derivatives are discussed which are said to be effective as sodium channel blockers.

It is an object of the invention to provide new Navi.g channel modulators which are good drug candidates. Preferred compounds should bind strongly to the Navi.g channel while displaying little affinity for other 3 sodium channels, in particular the TTX-S channels, and show functional activity as Navie channel modulators. They should be well absorbed from the gastrointestinal tract, be metabolically stable and have beneficial pharmacokinetic properties. They must be non-toxic and have few side effects. Furthermore, the ideal roedicament candidate exists in a physical form that is stable and non-hygroscopic and that can be easily formulated. Preferred pyrazine derivatives of the present invention are selective for the Navi.e channel relative to the tetradotoxin sensitive (TTX-S) sodium channels, leading to improvements in the side-effect profile.

The pyrazine derivatives of the present invention may therefore be useful in the treatment of a wide range of conditions, in particular pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, including postoperative pain and mixed pain types that include the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spinal cord, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.

Other disorders that can be treated with the pyrazine derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, gastric irritation syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional gastric disorders, gastric inflammatory diseases, pain associated with dysmenorrhea, pelvis pain , cystitis, pancreatitis, migraine, cluster and tension headache, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromylagia and causalgia.

The invention provides a pyrazine derivative of the formula (I): HN ^^ R1 Λ * Ν'γΛ'ΝΗ2

Ar 4 or a pharmaceutically acceptable salt or solvate thereof; wherein R 1 is a 5 membered heteroaryl group comprising either (a) 1 to 4 nitrogen atoms or (b) a acid or a sulfur atom and 0, 1 or 2 nitrogen atoms, optionally substituted with one or more subsituents each independently selected from 5 (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halogen (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy (C 1 -C 4 alkyl), amino (C 1 -C 4) alkyl, amino, (C 1 -C 4) ) alkylamino, di ((C 1 -C 4) alkyl) amino, (C 1 -C 4) alkylamino (C 1 -C 4) alkyl and di ((C 1 -C 4) alkyl) amino (C 1 -C 4) alkyl, with the proviso that R 1 is not imidazolyl, oxazolyl or 1,2,4-triazolyl;

Ar 10: 260; οόο * 260, where - * · indicates the point of attachment to the pyrazage; and each R 2 is independently selected from hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halogen (C 1 -C 4) alkyl, halogen (C 1 -C 4) alkoxy, cyano and halogen.

In the foregoing definitions, halogen means fluoro, chloro, bromo or iodo. Alkyl and alkoxy groups, which contain the required number of carbon atoms, can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Examples of haloalkyl include trifluoromethyl.

Specific examples of R 1 include thienyl, furanyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl (each optionally substituted as indicated above).

In a preferred aspect (A), the invention provides a pyrazine derivative of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is 5 and R1 and R2 are as defined above; more preferably, Ar is 2-chlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichloro-3-methoxyphenyl, 2,3,5-trichlorophenyl, 2-chloro-5-methoxyphenyl, 2.3 -dichloro-5-methoxyphenyl or 2-chloro-5-5 cyanophenyl.

In a preferred aspect (B), the invention provides a pyrazine derivative of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is as defined above, either in its broadest aspect or in a preferred aspect under (A) ; and R 1 is pyrazolyl or isoxazolyl, each of which is optionally substituted with (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy (C 1 -C 4) alkyl; more preferably, R 1 is pyrazolyl or isoxazolyl, each of which is substituted with one, two or three substituents independently selected from methyl, ethyl, and isopropyl; preferred individual R1 groups are 3-methylisoxazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 5-isopropylisoxazol-4-yl, 5-methylisoxazol-4-yl or 3-ethyl- 5-methylisoxazol-4-15 yl.

In a preferred aspect (C), the invention provides a pyrazine derivative of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar and R1 are as defined above, either in their broadest aspects or in a preferred aspect under (A) ) or (B), and each R 2 is independently selected from hydrogen, methoxy, ethoxy, cyano, methyl, ethyl, trifluoromethyl, trifluoromethoxy, chloro and fluoro; more preferably, each R 2 is independently selected from hydrogen, methoxy, cyano, trifluoromethyl, chlorine, and fluorine.

Preferred specific pyrazine derivatives according to the invention are those mentioned in the Examples section below and the pharmaceutically acceptable salts and solvates thereof. Even more preferred pyrazine derivatives of the invention are those selected from: N- [6-amino-5- (2,3-dichlorophenyl) pyrazin-2-yl] -3-methylisoxazole-4-carboxamide; N- [6-amino-5 - (2,5-dichlorophenyl) pyrazin-2-yl] -3-methylsoxazole-4-carboxamide; N- [6-amino-5- (2,5-dichloro-3-methoxyphenyl) pyrazol-2-yl] -3-methylisoxazole-4-30 carboxamide; N- [6-amino-5- (2,3-dichloro-5-methoxyphenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-carboxamide; N- [6-amino-5- (2-chlorophenyl) pyrazin-2-yl] -5-isopropylisoxazole-4-carboxamide; 6 N- [6-amino-5- (2-chlorophenyl) pyrazin-2-yl] -3-methylisoxazole-4-carboxamide; N- [6-amino-5- (2,3,5-trichlorophenyl) pyrazin-2-yl] -5-methylisoxazole-4-carboxamide; N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazine-2-yl] -3-methylisoxazole-4-carboxamide; 5 N - [6-amino-5- (2-chloro-5-cyanophenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-carboxamide; N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazine-2-yl] -3-ethyl-5-methylisoxazole-4-carboxamide; N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-10 carboxamide; N- [6-amino-5- (2,5-dichlorophenyl) pyrazin-2-yl] -1-methylMH-pyrazole-5-carboxamide; and N- [6-amino-5- (2 "Chloro-5-methoxyphenyl) pyrazine-2-yl] -5-isopropylisoxazole-4-carboxamide; IS and the pharmaceutically acceptable salts or solvates thereof.

The compounds of formula (I), which are Navi.g channel modulators, may be useful in the treatment of a range of conditions. The treatment of pain, in particular chronic, inflammatory, neuropathic, nociceptive and visceral pain, is a preferred application.

Physiological pain is an important protective mechanism designed to warn against the risk of potential injury stimuli from the external environment. The system works through a specific range of primary sensor neurons and is triggered by harmful stimuli via peripheral transduction mechanisms (see Millan, 1999, Prog. Neurobiol., 57.1-164 for an overview). These sensor fibers are known as nociceptors and are axons with a characteristic small diameter with low conduction rates. Nociceptors encode the intensity, duration and quality of the harmful stimulus and because of its topographically organized projection on the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibers, of which there are two main types, A-delta fibers (myelinated) and C-fibers (non-myelinated). The activity generated by nociceptor input is transmitted, after complex processing in the dorsal horn, either directly or via transducers of the brain stem, to the ventrobasal thalamus and then to the cortex, where the feeling of pain is generated.

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Pain can generally be classified as acute or chronic. Acute pain starts suddenly and is of short duration (usually twelve weeks or less). This is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the type of pain that can occur after specific injuries that are the result of surgery, dental work, a strain or a sprain. Acute pain generally does not result in a sustained psychological response. In contrast, chronic pain is long-term pain, which usually lasts longer than three months and leads to significant psychological and emotional problems. General examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, post-herpetic neuralgia), carpal canal syndrome, back pain, headache, pain due to cancer, arthritis pain and chronic pain after surgery.

If a significant injury to the body tissue occurs, through disease or trauma, the characteristics of nociceptor activation are altered and there is feeling in the periphery, locally around the injury and centrally where the nocideptors end. These effects lead to an increased feeling of pain. In the case of acute pain, these mechanisms can be useful, by promoting protective behavior, so that the recovery process can take place better. The normal expectation is that the sensitivity returns to normal once the injury has healed. In many chronic pain states, however, the hypersensitivity lasts much longer than the healing process and this is often the result of an injury to the nervous system. This injury often leads to sensor nerve fiber abnormalities associated with poor adaptation and abnormal activity (Woolf & Salter, 2000, Science, 288.1765-1768).

Clinical pain is present if discomfort and abnormal sensitivity are part of the patient's symptoms. Patients are quite heterogeneous and can have different pain symptoms. Such symptoms include: 1) spontaneous pain that can be dull, burning or stabbing; 2) exaggerated pain responses to harmful stimuli (hyperalgesia); and 3) pain produced by usually 30 harmless stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from different forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and, therefore, require different treatment strategies. Pain can therefore also be divided according to different pathophysiology into a number of different subtypes, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause an injury. Pain afferents are activated by the transduction of stimuli by nociceptors at the site of the injury and activate neurons in the spinal cord at the level of their termination. This is then passed through the spinal cord to the brain, where pain is encountered (Meyer et al., 1994, Textbook of Pain, 13-44. By activating nociceptors, two types of afferent nerve fibers 10 are activated. Myelinated A delta- fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, while non-myelinated C fibers transmit at a slower rate and cause dull or persistent pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from trauma of the central nervous system, strains / sprains, burns, heart attack and acute pancreatitis, pain after surgery (pain after any type of surgery), post-traumatic pain, renal colic, pain due to cancer and back pain Pain due to cancer can cause chronic pain such as pain associated with a tumor (eg bone pain, headache, facial pain or visceral pain) or pain associated with with cancer treatment (e.g. post-chemotherapy syndrome, chronic post-surgical pain syndrome or post-radiation syndrome). Pain due to cancer can also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiation therapy. Back pain may be due to hernia of the intervertebral discs or ruptured intervertebral discs or abnormalities of the lumberfacet joints, sacrum, hipbone joints, paraspinal muscles or the posterior longitudinal ligament. Back pain can naturally disappear in some patients, if it lasts longer than 12 weeks it becomes a chronic condition which can be particularly dragging.

Neuropathic pain is now defined as pain that is initiated or caused by a primary lesion or disorder in the nervous system. Nerve damage can be caused by trauma and disease and thus the term "neuropathic pain" includes many disorders with different aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal canal syndrome, central pain 9 after a stroke, and pain that is associated with chronic alcoholism hypothyroidemia, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. This is often present long after the original cause has disappeared, usually lasts for years and significantly reduces the quality of life of the patient (Woolf and Mannion, 1999, Lancet, 353,1959-1964). The symptoms of neuropathic pain are difficult to treat, since even among patients with the same disease they are often heterogeneous (Woolf & Decosterd, 1999, pain Supp., 6, S141-S147; Woolf and mannion, 1999, Lancet, 353, 1959- 1964). These include spontaneous pain, which may be continuous, and paroxysmal or abnormally induced pain, such as hyperalgesia (increased sensitivity to a harmful stimulus) and allodynia (sensitivity to a usually harmless stimulus).

The inflammatory process is a complex series of biochemical and cellular events, triggered in response to tissue injury or the presence of foreign substances, resulting in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56) . Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It is estimated that about 16 million Americans have symtomatic osteoarthritis (OA) or degenerative joint disease, most of which are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this an audience health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical care because of the associated pain. Arthritis has a significant influence on psychosocial and physical function and it is known that this is the main cause of disability in later life. Spondylosis ankylopoietics is also a rheumatic disease that causes arthritis of the spine and sacrum hip bone joints. This varies from interrupted episodes of back pain that occur during life to a serious chronic disease that affects the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain, which includes pain associated with gastric inflammatory disease (IBD). Visceral pain is pain associated with the viscera, which includes the organs of the abdominal cavity. These organs include the reproductive organs, spleen and parts of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Gastrointestinal (GI) disorders that cause pain and that are commonly encountered include functional stomach disorder (FBD) and gastric inflammatory disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, with regard to FBD, gastroesophageal reflux, dyspepsia, gastric irritation syndrome (IBS) and functional gastric pain syndrome (FAPS), and, with regard to IBD , Crohn's disease, ileitis and ulcerative colitis, all of which regularly cause visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis, and pelvis pain.

It should be noted that some types of pain have multiple aetiologies and can therefore be classified into more than one area, e.g. Back pain and pain due to cancer have both nociceptive and neuropathic components.

Other types of pain include: • pain resulting from musculoskeletal disorders, including myalgia, fibromalgia, spondylitis, sero-negative (non-rheumatic) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, and pyomyositis; • heart and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, and musculoskeletal ischemia; • headache, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension type headache, mixed headache and headache associated with vascular disease; and • orofacial pain, including toothache, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

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The pyrazine derivatives of formula (I) are also expected to be useful in the treatment of multiple sclerosis.

The invention also relates to the therapeutic use of the pyrazine derivatives of the formula (I) as agents for treating or alleviating the symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. The present invention also includes treating neurodegenerative disorders referred to as acute brain injury. These include, but are not limited to: stroke, head trauma and suffocation. Stroke refers to a cerebral vascular disorder and can also be referred to as a cerebral vascular accident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also included are temporary cerebral ischemia attacks and other cerebral vascular problems associated with cerebral ischemia. These vascular disorders may occur in a patient having carotid endarterectomy in particular or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures, including cerebral angiography and the like. Other events include head trauma, spinal cord trauma, or an injury of general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during embolism, hyperfusion and hypoxia. The present invention is useful in a range of events, such as during cardiac bypass surgery, intracranial bleeding events, perinatal asphyxiation, cardiac arrest and status epileptic.

A physician can determine the correct situation where individuals are susceptible to or at risk of, for example, a stroke as well as suffering from a stroke for administration according to the methods of the present invention.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, hydrogen carbonate / carbonate, hydrogen sulfate / sulfate, borate, camsylate, citrate, 12 cyclamate, edisylate, esylate, formate, fumarate, glucepate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isothionate, lactate, malate, maleate, malonate, mesylate , methylsulfate, naphlylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinophoate salts.

Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemi salts of acids and bases can also be formed, such as, for example, hemisulfate and hemicalcium salts.

For an overview of suitable salts see Handbook of Pharmaceutical Salts: 15 Properties. Selection and Use of Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) can be prepared according to one or more of three methods: (i) reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I); or (iii) by converting a salt of the compound of formula (I) into another by reaction with a suitable acid or base or by means of a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt obtained can vary from fully ionized to virtually non-ionized.

The compounds of the invention may exist in a solid state continuum ranging from completely amorphous to fully crystalline. The term "amorphous" refers to a state in which the material lacks long-distance order at the molecular level and, depending on the temperature, may exhibit the physical properties of a solid or liquid. Typically, such materials do not give clear X-ray diffraction patterns and, while displaying the properties of a solid, are more formally described as a liquid. During heating, a change from solid to liquid properties takes place which is characterized by a change of state, usually of the second order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a clear X-ray diffraction pattern with defined peaks. Such materials, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, usually of the first order ("melting point").

The compounds according to the invention can also exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water.

A currently accepted classification system for organic hydrates is a system that defines hydrates with an isolated site, channel hydrates or metal ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids of K.R. Morris (Ed. H.G. Brittain, Marcel Dekker, 1995). Hydrates with an isolated site are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In the case of channel hydrates, the water molecules are located in lattice channels, where they are located next to other water molecules. In hydrates coordinated with a metal ion, the water molecules are bound to the metal ion.

When the solvent or water is tightly bound, the complex has a well-defined stoichiometry which is independent of the humidity. However, if the solvent or water is weakly bound, such as with channel solvates and hygroscopic compounds, the water / solvent content is dependent on the humidity and drying conditions. In such cases, non-stoichiometry is the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates), wherein the medicament and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are usually defined as crystalline complexes of neutral molecular components that are bound to each other via non-covalent interactions, but can also be a complex of a neutral molecule with a salt. Co-crystals can be prepared by melt crystallization, by recrystallization from solvents or by physically grinding the components together - see Chem Commun, 17, 1889-1896, from O. Almarsson and M.J. Zaworotko (2004). For a general overview of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, 15 by Haleblian (August 1975).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) if they are subjected to suitable conditions. The mesomorphic state is between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism that arises as a result of a temperature change is described as "thermotropic" and mesomorphism that results from the addition of a second component, such as water or another solvent, is described as lyotropic. Compounds that have the ability to form lyotropic mesophases are described as "amphiphilic" and consist of molecules that are ionic (such as -COO'Na *, -COO'K1 or -SOj-Na *) or non-ionic (such as -ΝΊΜ * (013) 3) polar head group. For more information see Crystals and the Polarizing Microscope by N.H. Hartshome and A. Stuart, fourth edition (Edward Arnold, 1970).

Hereinafter, all references to compounds of formula (I) include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, including ale polymorphs and crystal embodiments thereof, promedicaments and isomers thereof (including optical, geometric and tautomeric isomers), as defined below, and isotope-labeled compounds of the formula (I).

As shown, so-called promedicaments of the compounds of the formula (I) also fall within the scope of the invention. Thus, certain derivatives of compounds of formula (I) which themselves have little or no pharmacological activity can, when administered to or on the body, be converted by compounds such as hydrolytic cleavage into compounds of formula (I) with the desired activity. Such derivatives are referred to as 10 'promedicaments'. Further information regarding the use of promotional drugs can be found in Prodrues as Novel Delivery Systems, part 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Promedicaments according to the invention can be prepared, for example, by replacing suitable functionalities present in the compounds of the formula (I) with certain residues known to those skilled in the art as "pro-residues", as described for example in Design or Prodrus from H. Bundgaard (Elsevier, 1985).

Some examples of promedicaments according to the invention include, if the compound of the formula (I) contains a primary or secondary amino functionality (-NH 2 or -NHR, wherein R 1 H), an amide thereof, for example a compound wherein, such as the case may be that one or both of the hydrogen atoms of the amino functionality of the compound of the formula (I) has been replaced by (C 1 -C 10) alkanoyl.

Further examples of replacement groups according to the preceding examples and examples of other promedicament types can be found in the aforementioned references.

Furthermore, certain compounds of the formula (I) may themselves act as promicaments of other compounds of the formula (I).

Also included within the scope of the invention are metabolites of compounds of the formula (I), that is, compounds formed in vivo upon administration of the medicament. Some examples of metabolites according to the invention include (i) if the compound of the formula (I) contains a methyl group, a hydroxymethyl derivative thereof ((-CH 3 -> -CH 2 OH): (ii) as the compound of the formula ( I) contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH), (iii) if the compound of the formula (1) contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2) and (iv) if the compound of formula (I) contains a phenyl radical, a phenolic derivative thereof (-Ph -> - PhOH).

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Compounds of the formula (I) which contain one or more asymmetric carbon atoms may exist as two or more stereoisomers. If structural isomers can be converted into each other via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This may take the form of so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound can exhibit more than one type of iomeria. Included within the scope of the present invention are all stereoisomers and tautomeric forms of the compounds of formula (I), including compounds that exhibit more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition and base salts wherein the counter ion is optically active, such as, for example, d-lactate or 1-lysine, or is racemic, such as, for example, dl tartrate or dl arginine.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or dissolving the racemic mixture (or the racemic mixture of a salt or derivative) using, for example, chiral high-pressure liquid chromatography ( HPLC).

17

In addition, the racemic mixture (or a racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or, in the case that the compound of the formula (I) contains an acid or basic residue, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric human can be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers can be converted to the pure enantiomer / enantiomers in a manner known to the skilled person.

Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, usually HPLC, over an asymmetric mobile phase resin consisting of a hydrocarbon, usually heptane or hexane, which is 0 to 50 vol%, usually 2 vol% to 20 vol% isopropanol and 0 to 5 vol% of an alkylamine, usually 0.1 vol% diethyl amine. Concentration of the eluate gives an enriched mixture.

Crystals of two different types are possible as a racemic mixture. The first type is the racemic compound (actual racemate) referred to above, wherein a homogeneous form of the crystal is prepared containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate, wherein two forms of the crystal are prepared in equimolar amounts, each comprising a single enantiomer.

While both crystal forms present in a racemic mixture have identical physical properties, they can have different physical properties compared to the actual racemic mixture. Racemic mixtures can be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds from E.L. Eliel and S.H. Wilen (Wiley, 1994).

The present invention encompasses all pharmaceutically acceptable isotope-labeled compounds of the formula (I), wherein one or more atoms have been replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature .

Examples of isotopes suitable for incorporation into the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 18 nC, 13 C and 14 C, chlorine such as 36 Cl, fluorine such as 18 F, iodine, such as 123 I and 12 I nitrogen, such as 13 N and 13 N, oxygen such as 150,170 and 180, phosphorus such as 32 P, and sulfur such as 35 S.

Certain isotope-labeled compounds of formula (I), for example, those comprising a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose with regard to their ease of incorporation and suitable means of detection thereof.

Substitution with heavier isotopes such as deuterium, i.e., H, may provide certain therapeutic benefits due to the greater metabolic stability, such as, for example, a greater in vivo half-life or lower dose, and thus may be preferred in some cases.

Substitution with positron-emitting isotopes, such as nC, 18F, 150 and 13N, may be useful in Positron Emission Topography (PET) studies for investigating substrate-receptor occupation.

Compounds of the formula (I) labeled with isotopes can generally be prepared by conventional techniques known to the person skilled in the art or by methods analogous to the methods described in the accompanying examples and preparations using a suitable method, isotope-labeled reagent instead of the non-labeled reagent previously used.

Pharmaceutically acceptable solvates according to the invention include those wherein the crystallization solvent may be substituted with isotopes, e.g. D2O, de-acetone, dö-DMSO.

Also, new intermediate compounds as defined below, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as hereinbefore defined for compounds of formula (I) are within the scope of the invention. The invention includes all polymorphs of the aforementioned species and crystal embodiments thereof.

The compounds of the formula (I) should be tested for their biopharmaceutical properties, such as solubility and solution stability (over the pH), permeability, etc., for choosing the most appropriate dosage form and route for treatment of the proposed indication .

19

Compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders or films, according to methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying.

Microwave or radio frequency drying can be used for this purpose.

They can be administered individually or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). In general, they are administered as a formulation together with one or more pharmaceutically acceptable excipients.

The term "excipient" is used herein to describe a component other than the compounds of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability and the nature of the dosage form.

Pharmaceutical compositions suitable for the release of compounds of the present invention and methods for their preparation are known to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19c edition (Mack Publishing Company, 1995).

The compounds of the invention can be administered orally. Oral administration may swallow, so that the compound enters the gastrointestinal tract, and / or buccal, lingual or sublingual administration, wherein the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems, such as tablets; soft and hard capsules containing multi or nano particles, liquids or powders; cough tablets (including liquid-filled); chew formulations; gels; fast dispersing dosage forms; films; ovula; sprays; and buccal / mucosal adhesive plasters.

Liquid formulations include suspensions, solutions, syrups and elixirs.

Such formulations can be used as fillers in soft or hard capsules (made for example from gelatin or hydroxypropyl methylcellulose) and usually include a carrier, e.g. water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or an appropriate oil, and one or more emulsifying Liquid formulations and / or suspending agents. Liquid formulations can also be prepared by the reconstitution of a solid, for example from an ampoule.

The compounds of the invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, ü (6), 981-986, by Linag and Chen (2001).

For tablet dosage forms, depending on the dose, the medicament may be 1 wt% to 80 wt% of the dosage form, more usually 5 wt% to 60 wt% of the dosage form. In addition to the medicament, tablets generally contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch and sodium alginate. In general, the disintegrant comprises 1 wt% to 25 wt%, preferably 5 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesion properties to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pre-gelled starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tables may optionally also include surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. If present, the surfactants may comprise from 0.2% by weight to 5% by weight of the tablet and the lubricants may comprise from 0.2% by weight to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight, preferably 0.5% by weight to 3%. % by weight of the tablet.

21

Other possible ingredients include antioxidants, colorants, flavors, preservatives, and flavor masking agents.

Examples of tablets include up to about 80% medicament, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25 wt% to about 10 wt% of lubricant.

Tablet mixtures can be compressed directly or with a roller to form tablets. Tablet mixtures or parts of mixtures can additionally be granulated wet, dry or in the melt, frozen in the melt or extruded for tableting. The final formulation can include one or more layers and can be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, part 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are usually flexible, water-soluble or water-swellable thin film-shaped dosage forms that can be rapidly dissolving or mucosal and usually comprise a compound of formula (I), a film-forming polymer, a binder , a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the formulation can perform more than one function.

The compound of the formula (I) can be water-soluble or insoluble. A water-soluble compound usually comprises 1 wt% to 80 wt%, more usually 20 wt% to 50 wt% of the dissolved components. Less soluble compounds may comprise a higher content of the composition, usually up to 88% by weight of the dissolved components. In addition, the compound of formula (I) may be in the form of multi-particle granules.

The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is usually present in the range of 0.01 to 99% by weight, more usually in the range of 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils), softeners, ballasts, antifoams, surfactants, and flavor masking agents.

Films according to the invention are usually prepared by evaporative drying of thin aqueous films which are coated on a peel coating or S paper. This can be done in a drying oven or tunnel, usually a combined coating machine dryer, or by freeze drying or suctioning.

Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified-release formulations include delayed, sustained, pulse-shaped, controlled, targeted, and programmed release.

Suitable modified-release formulations for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable delivery technologies such as high-energy dispersions and osmotic and coated particles can be found in Pharmaceutical Technology On-line 25 (2). ), 1-14, by Verma et al. (2001). The use of chewing gum for achieving controlled release is described in WO 00/35298.

The compounds of the invention can also be administered directly to the blood stream, including muscles, or to an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intra-urethral, intrastemal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injection, needle free injection and infusion techniques.

Parenteral formulations are usually aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably up to a pH of 3 to 9), but for some applications they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable medium such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily accomplished using standard pharmaceutical techniques known to those skilled in the art.

23

The solubility of compounds of formula (I) used in the preparation of paienteral solutions can be increased by the use of suitable formulation techniques, such as incorporating solubility enhancing agents.

Formulations for parenteral administration can be formulated for immediate release and / or modified release. Modified-release formulations include delayed, sustained, pulse-shaped, controlled, targeted, and programmed release. Thus, compounds of the invention can be formulated as a suspension or as a solid, semi-solid or thixotropic liquid for administration as an implanted depot that provides for the modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded microspheres of poly (dl-milk-co-glycol) acid (PGLA).

The compounds of the invention may also be administered topically, (intra) dermally or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, waffles, implants, sponges, fibers, dressings and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, inorganic oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol.

Penetration enhancing agents may be included - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle free (e.g., Powderject ™, Bioject ™, etc.) injection.

Formulations for topical administration can be formulated for immediate and / or modified release. Modified-release formulations include delayed, sustained, pulse-shaped, controlled, targeted, and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (either separately, as a mortar, for example in a dry mixture with lactose, or as a particle of mixed components, for example mixed with phospholipids, such as phosphatidylcholine from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer employing electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-5 tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, spray or nebulizer contains a solution or suspension of the compound (s) according to the invention, which for example contains ethanol, aqueous ethanol, or a suitable alternative means for dispersing, dissolving or extending the release of the active agent, a propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

For use in a dry powder or suspension formulation, the product is microfine made to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by a suitable comminution method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (for example made from gelatin or hydroxypropyl methylcellulose), blister packs and fillings for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and an agent for the modify the behavior such as 1-leucine, mannitol or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain 1 to 30 mg to 20 mg of the compound of the invention per operation and the operation volume may vary from 1 μ to 100 μΐ. A conventional formulation may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Other solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents, such as menthol and levomenthol, or sweetening agents, such as saccharin or saccharin sodium, can be added to the formulations of the invention intended for inhaled / intranasal administration.

Formulations for inhaled / intranasal administration may be formulated using, for example, PGLA, for immediate and / or modified release. Modified-release formulations include delayed, sustained, pulse-shaped, controlled, targeted, and programmed release.

In the case of dry powder inhalers and aerosols, the administration unit is determined by means of a valve which delivers a metered amount. Units of the invention are usually arranged to administer a metered dose or "puff." The total daily dose can be administered in a single dose or, more usually, as divided doses during the day.

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used if desired.

Formulations for rectal / vaginal administration can be formulated, for immediate release and / or modified release. Modified-release formulations include delayed, sustained, pulse-shaped, controlled, targeted, and programmed release.

The compounds of the invention can also be administered directly to the eye or ear, usually in the form of drops of a microfine-made suspension or solution in an isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. polysiloxane) implants, waffles, lenses, and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, can be included together with a preservative such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

Formulations for ocular / aural administrations can be formulated for immediate release and / or modified release. Modified-release formulations include delayed, sustained, pulse-shaped, controlled, targeted, and programmed release.

The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve solubility, dissolution rate, taste masking, bioavailability and / or stability thereof for use in one of the aforementioned methods of administration.

For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solvent. For this, alpha, beta and gamma cyclodextrins are usually used, examples of which can be found in International Patent Applications WO 91/11172, WO 94/0258 and WO 98/55148.

For administration to human patients, the total daily dose of the compounds of the invention is usually in the range of 0.1 mg to 1000 mg, depending, of course, on the method of administration. The total daily dose can be administered in single or divided doses and, at the physician's discretion, may fall outside the usual range provided herein.

These doses are based on an average human object with a weight of approximately 60 kg to 70 kg. The physician can easily determine doses for objects whose weight falls outside this range, such as infants and the elderly.

For the avoidance of doubt, references herein to "treatment" include references to healing, palliative, and prophylactic treatment.

27

A Navi g channel modulator can be conveniently combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. For example, a Navis channel modulator, in particular a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, can be simultaneously, sequentially or separately in combination with one or more agents. selected from: an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyfen, nalmefen, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbufine or pentazopine; A non-steroidal anti-inflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, fluriottal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumeton, naproxen, nimesuliphenic, oliproziprof, nitrofzalin, oliproziprof, nitroprazole , tolmetine or summer piracy; A barbiturate tranquilizer, e.g. amobarbital, aprobarbital, butabarbital, butabital, mefobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, theamylal or thiopental; A benzodiazepine with a calming effect, e.g. chlorodiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oazepam, temazepam or triazolam; A Hi antagonist with a calming effect, e.g. diphenylhydramine, pyrilamine, promethazine, chloropheniramine or chlorcyclozine; A tranquilizer such as glutethimide, meprobamate, methaqualon or dichloro-la-phenazone; A relaxant for skeletal muscles, e.g. baclofen, carisoprodol, chloroxoxazone, cyclobenzaprine, methocarbamol or orfrenadine; An NMDA receptor antagonist, e.g. dextromethorphan ((+) - 3-hydroxy-N-methylmorphan) or its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphan), ketamine, memantine, pyrroloquinoline quinine, cis-4-28 (phosphonomethyl) -2 -piperidine carboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or peizinfotel, including an NR2B antagonist, eg ifenprodil, traxoprodil or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl] -1-5 hydroxyethyl-3,4-dihydro-2 (1H) quinoline; An alpha-adienergic compound, e.g. doxazosin, tamsulosin, clonidine, guanfacin, dexmetatomidine, modanil or 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline; A tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline; An anticonvulsant agent, e.g. carbamazepine, lamotrigine, topirate or valproate; A trachykinin (NK) antagonist, in particular an NK-3, NK-2 or NK-1 antagonist, e.g. (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2, 18] [1,7] naphthyridine-6-1,3-dione (TAK-637), 5 - [[(2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3 H -1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant dapitant or 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] methylamino] -2-phenylpiperidine (2S, 3S); A muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temierine and ipratropium; A COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib; A coal tar analgesic, in particular paracetamol; · A neuroleptic drug such as droperidol, chlooipromazine, helopeidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, flufenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blopanseripine, zeroprotone, zeroprotone, ropiron, seropine, ripone, seropine, seropine , lurasidone, amisulpride, balaperidone, palindor, eplivanserine, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan; A vanilloid receptor agonist (e.g., resin feratoxin) or antagonist (e.g., capsazepine); A beta-adrenergic compound such as propanolol; • a local anesthetic such as mexiletine; A corticosteroid such as dexamethasone; A 5-HT receptor agonist or antagonist, in particular a 5-HT 1B / iD agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; · A 5-HT 2A receptor antagonist such as R (+) - alpha (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenylethyl)] -4-piperidinemethanol (MDL-100907); A cholinerg (nicotine) analgesic such as ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-butene-1-amine (RJR-2403), (R) -5 - (2-azetidinyl-methoxy) -2-chloropyridine (ABT-594) or nicotine; Tramadol®; A PDEV inhibitor, such as 5- [2-ethoxy-5- (4-methyl-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7 H -pyrazole [4,3- d] pyrimidin-7-one (sildenafil), (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-inethyl-6- (3,4-methylenedioxyphenyl) pyazino [2 ,, Γ : 6.1] pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl-1-sulfonyl) ) phenyl] -5-methyl-7-propyl-3 H -imidazo [5,1f] [1,2,4] triazine-4-one (vardenafil), 5- (5-acetyl-2-butoxy-3-pyridinyl) ) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7 H -pyrazole [4,3-d] pyriimidine-7-one, 5- (5-acetyl-2-) propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7 H -pyrazole [4,3-d] pyrimidine-7-one, 5- [2- ethoxy-5- (4-20 ethylpiperazine-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7 H -pyrazole [4,3-d] pyrimidine -7-one, 4 - [(3-chloro-4-methoxybenzyl) -amino] -2 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidin-2-ylmetliyl) - pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1 H -pyr α-sol [4,3-d] pyrimidin-5-yl) -N- [2- (1-methylpyridin-2-yl) ethyl] -4-25 propoxybenzenesulfonamide; An alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1a, 3a, 5a) (3-aminomethylbicyclo [3.2.0] hept-3-yl) acetic acid, (3S, 5R) -3- amino-methyl-5-methylheptanoic acid, (3S, 5R) -3-amino-5-methylheptanoic acid, (3S, 5R) -3-amino-5-methyloctanoic acid, (2S, 4S) -4- (3-chlorophenoxy) proline , (2S, 4S) -4- (3- fluorobenzyl) proline, [(1R, 5R, 6S) -6- (ammomethyl) bicyclo [3.2.0] hept-6-yl] - acetic acid, 3- (1 -aminomethylcyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) cycloheptyl] methylamine5 (3S, 4S) - (1-aminomethyl-3, 4-dimethylcyclopentyl) acetic acid, (3S, 5R) -3-aminomethyl-5-methyl octanoic acid, (3S, 5R) -3-amino-5-methyl nonanoic acid, (3S, 5R) -3-amino-5 -methyloctanoic acid, (3R, 4R, 5R) -3-amino-4,5-dimethylheptanoic acid and (3R, 4R, 5R) -3-amino-4,5-dimethyloctanoic acid; • a cannabinoid; Metabotropic glutamate subtype 1 receptor (mGluR1) antagonist; • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite, demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite, desmethylcitalopram, escitalopram, d, loxetine, ifhenoxetine, foxetine, cothenoxine, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone; • a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotilin, fezolamine, tomoxetine, mianserine, bupropion, bupropion metabolite, hydroxybupropion, nomifensin and viloxazine (Vivalan®), especially inhibitory re-uptake Such as reboxetine, in particular (S, S) reboxetine; A dual serotonin noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipamine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine; · An inducible nitric oxide synthase (iNOS) inhibitor such as S- [2 - [(1-iminoethyl) amino] ethyl] -L-homocysteme, S- [2 - [(1-iminoethyl) amino] ethyl] -4, 4-dioxo-L-cysteine, S- [2 - [(1-iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2-methyl-7 - [( 1-iminoethyl) aimno] -5-hepttenic acid, 2 - [[(1R, 3S) -3-amino-4-hydroxy-1 - (5-thiazolyl) butyl] thio] -5-chloro-3-pyridinecarbonitrile; 2- [[(1 R, 3 S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -4-chlorobenzonitrile, (2S, 4 R) -2-amino-4 - [[2-chloro- 5- (trifluoromethyl) phenyl-thio] -5-thiazole-butanol, 2 - [[(1 R, 3 S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -6- (trifluoromethyl) -3- pyridinecarbonitrile, 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) ethyl] ] phenyl] thiophene-2-carboxamidine or guanidinoethyl disulfide; An acetylcholine stearase inhibitor such as donepezil; A prostaglandin E1 subtype 4 (EP4) antagonist such as N - [({2- [4- (2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl)) phenyl] ethyl} amino) carbonyl] -4-methyl-benzenesulfonamide or 4 - [(1S) -1 - ({[5-chloro-2 (3-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; • a leukotriene B4 antagonist; such as 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl)] ) -5E-hexenyl] oxyphenoxy] valeric acid (ONO-4057) or Ι Ι 1870, • a 5-lipoxygenase inhibitor, such as zileutone, 6 - [(3-fluoro-5- [4-methoxy-3,4,5)] 6-tetrahydro-2 H -pyran-4-yl] phenoxymethyl] -1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6- (3-pyridylmethyl) -1,4- benzoquinone (CV-6504); A sodium channel blocker, such as lidocaine; A 5-HT3 antagonist, such as ondansetron; and the pharmaceutically acceptable salts and solvates thereof.

Such combinations offer significant benefits, including synergistic activity, in the treatment.

To the extent that it is desirable to administer a combination of active compounds, for example for treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which is a compound according to the invention, can be suitably combined in the form of a kit suitable for co-administration of the compositions.

The kit according to the invention thus comprises two or more separate pharmaceutical compositions, at least one of which comprises a compound of the formula (I) according to the invention, and means for keeping the compositions separate, such as a container, divided bottle or distributed foil package. An example of such a kit is the well-known blister pack used for packaging tablets, capsules and the like.

The kit according to the invention is particularly suitable for administering different dosage forms, for example orally and parenterally, for administering the individual compositions with different application intervals or for titrating the individual compositions against each other. To assist with compliance, the kit usually includes directions for administration and may be provided with a so-called memory aid.

32

All pyrazine derivatives of the formula (I) can be prepared according to the methods described in the general methods described below or by routine modifications thereof. The present invention also encompasses one or more of these processes for preparing the pyrazine derivatives of formula 5 (I), in addition to novel intermediates used herein.

In the following general methods, Ar and R1 are as defined above for a pyrazine derivative of formula (I) unless otherwise stated. If ratios of solvents are given, these ratios are volume ratios.

According to a first method, compounds of the formula (I) can be prepared from compounds of the formula (V), as illustrated in scheme 1.

O

YOU

o nh2 o nh2 o hn r1 II N i ΟΗ »νο''γ ^ Ν» "Υ ^ νη," 'Λν * ny ^ nh2 xl λγ V o Ar <")“ (III) r-Ay (IV) S 9 O HN R1 u. | Ai

II I HN R

—HoVj ^ X

NrV ν-Λνη2

Ar Ar (V) (I)

Scheme 1 M is an optionally substituted metal or boron group that is suitable for cross-linking reactions, such as trialkylstannane, dihydroxyborane, dialkoxyborane or halogen zinc.

X is a suitable group for cross-coupling reactions, usually Cl, Br or I.

Y is a suitable leaving group, usually Cl.

33

Compounds of the formula (II) are either commercially available, in the case of the chlorine derivative, or are known from the literature (J. Med. Chem. 1967, 10 (1), 66-75).

Compounds of the formula (ΙΠ) can be prepared from compounds of the formula (II) by process step (i), a cross-coupling reaction, with ArM, in the presence of a suitable catalyst system (e.g. palladium or nickel) and base. Typically, "Suzuki" conditions are used, which are 1.2-3 equivalents of boric acid, base and 0.01-0.25 equivalents of a palladium catalyst with phosphine-based ligands in an organic solvent at a temperature of 50 ° C to 100 ° C. Preferred conditions include 2 equivalents of boric acid, 1 equivalent of CS 2 CO 3 and 0.1 equivalent of Pd (PPh 3) 4 in 2: 1 1,4-dioxane / water at 80 ° C.

Compounds of the formula (IV) can be prepared from compounds of the formula (ΠΙ) according to process step (ii), an amide coupling using an acid chloride or a carboxylic acid activated by a suitable agent, optionally in the presence of a catalyst, in a suitable solvent. Typical conditions include an acid chloride and an amine of formula (III), with an excess of a suitable organic base, such as Et 3 N, lutidine or pyridine, in a suitable solvent, at a temperature of room temperature to 80 ° C. Preferred conditions include 1.5 equivalents of acid chloride in pyridine at 60 ° C, or with 1.5 equivalents of lutidine in acetonitrile at room temperature.

Compounds of the formula (V) can be prepared from compounds of the formula (TV) according to process step (iii), an ester hydrolysis reaction under basic or acidic conditions. Conventional conditions are based on a base, using an alkali metal base such as LiOH, NaOH, KOH or K 2 CO 3 in the presence of water and a suitable solvent at a temperature of room temperature to 100 ° C. Preferred conditions include 3 equivalents of LiOH.H 2 O in 3: 1 CH 3 OH / H 2 O at 75 ° C.

Compounds of the formula (I) can be prepared from compounds of the formula (V) by decarboxylation under basic or acidic conditions where a temperature of 50 ° C to 150 ° C is required (process step (iv)). Typical conditions include an excess of an aqueous acid in a suitable organic solvent at a temperature of 50 ° C to 100 ° C. The 34 decarboxylation step is preferably carried out under reflux in 2: 1 IN aqueous HCl / 1,4-dioxane.

According to a second method, compounds of the formula (I) can be prepared from compounds of the formula (VII), as illustrated in scheme 2.

5 O NH 2 O NH, O NH, X v Ar Ar (11) V (III) (VI)

Ar

O

J] nh2 hn ^ r1

| f * N if ^ N

* 'o * (vu) R, XY (o

Scheme 2 where Μ, X and Y are as defined for scheme 1.

Compounds of formula (III) can be prepared from compound of formula (II) according to process step (i) as previously described for scheme 1.

Compounds of the formula (VI) can be prepared from compound of the formula (ΠΙ) by ester hydrolysis according to process step (iii) as described above for scheme 1.

Compounds of formula (VII) can be prepared from compound of formula (VI) by decarboxylation according to process step (iv) as previously described for scheme 1.

Compounds of the formula (I) can be prepared from compounds of the formula (VIII) by an amide coupling reaction according to process step (ii) as previously described for scheme 1.

35

Compounds of the formula (VII) can also be prepared according to a third method as described in WO-A-98/3817 (Scheme 3).

NH2 NH2 • 2hb; X: h w - Λ »(> i) Γ Λ L, ArCHO ΗΝγΟΝ

Ar Ar (VIII) (IX) (VII) 5

Schedule 3

Compounds of the formula (IX) can be prepared, according to process step (v), by reacting compounds of the formula (VIII) or a salt thereof, for example aminoacetamidine, with compounds of the formula ArCHO in the presence of a cyanide source, for example potassium cyanide.

Compounds of the formula (VII) can be prepared by cyclization and oxidation of a compound of the formula (IX) in the presence of lithium hydroxide in a suitable alcoholic solvent such as methanol, the reaction being open to the air for oxidation.

According to a fourth method, compounds of the formula (I) can be prepared from compounds of the formula (XII), as illustrated in scheme 4.

O nh 2 o nh 2 nh 2

CH3'o'AY ^ N (iii) a ΗΟ'γ'γ (iv) ^ (p ^ N

N ^ NH 2 nY ^ nh 2 ν-ννη 2

x XX

(II) (X) (XI) o o

u X

HN ^ R1 HN R1

-jiu rS _üu rS

r ~ νυ ^ νη2 r ~ νυ ^ νη2 l X \ Ar r, Ay <x «) l 0) 36

Scheme 4 X, X and Y are as defined for Scheme 1.

Compounds of the formula (X) can be prepared from compounds of the formula (Π) by ester hydrolysis according to process step (iii) as described above for scheme 1.

Compounds of the formula (XI) can be prepared from compounds of the formula (X) by decarboxylation according to process step (iv) as previously described for scheme 1.

Compounds of the formula (XII) can be prepared from a compound of the formula (XI) by an amide coupling reaction according to process step (ii) as previously described for scheme 1.

Compounds of the formula (I) can be prepared from compounds of the formula (XII) by a cross-coupling reaction according to process step (i) as previously described for scheme 1.

Compounds of the formula (XI) may additionally be prepared from compounds of the formula (XIII), as illustrated in Scheme 5.

nh2 nh2

Vi <viil ifS

n- ^ nh 2 N'Y? JvNH 2 (XII,) (XI)

Scheme 5 wherein X is a halogen atom.

2,6-diaminopyrazine can be prepared as described in J. Chem. Soc.

Perkin Trans. 1: Organic and Bio-Organic Chemistry (1972-1999) 1973, 6, 606.

Compounds of the formula (XI) can be prepared by an electrophilic halogen ring reaction according to reaction step (vii). Typical conditions include the reaction of 2,6-diaminopyrazine with a halogen, optionally in the presence of 37 a catalyst, e.g. iodine and silver acetate or bromine, in a suitable solvent. Preferred conditions include bromine in acetic acid at room temperature.

In addition, compounds of the formula (XII) can be prepared from compounds of the formula (XIV), as illustrated in Scheme 6.

5

O O

NH, HN ^ R 'HN- ^ R' ifS rS -? ÜL Λ n ^ nh2 νΥ ^ νπ2

(ΧΙΌ [O (XIV) X

βΛ (XII)

Scheme 6 wherein Y is as defined for scheme 1; and X is a halogen atom.

Compounds of the formula (XTV) can be prepared from compounds of the formula (XIII) by an amide coupling reaction according to process step (ii) as described for scheme 1.

Compounds of the formula (XII) can be prepared from compounds of the formula (XIV) by an electrophilic halogenation reaction according to process step (vii) as described for scheme 5.

It will be apparent to those skilled in the art that, in the foregoing general methods, where protecting groups are present, they are generally interchangeable with other protecting groups of a similar nature, e.g. where an amine is described as being protected by a tert-butoxycarbonyl group, it can be easily exchanged for any amine-protecting group. Suitable protecting groups are described in "Protective Groups in Organic Synthesis" by T. Greene and P. Wuts 25 (third edition, 1999, John Wiley and Sons).

The present invention also relates to novel intermediates as defined above, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as previously defined for pyrazine derivatives of the formula (I). The invention includes all polymorphs of the aforementioned species and crystal forms thereof.

In preparing pyrazine derivatives of the formula (I) according to the invention, it is up to a person skilled in the art to routinely choose the form of the intermediates which gives the best combination of characteristics for this purpose. Such characteristics include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product can be purified upon isolation.

The invention is illustrated in the following representative examples.

10 ^ nuclear magnetic resonance (NMR) spectra corresponded in all cases to the proposed structures. Typical chemical shifts (δ) are given in parts per million downstream of tetramethylsilane, using conventional abbreviations for indications of important peaks: e.g. s singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, wide. The mass spectra (MS) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). The following abbreviations have been used for conventional solvents: CDCl3, deuterochloroform; d ^ -DMSO, deuterodimethyl sulfoxide; CD3OD, deuteromethanol; THF, tetrahydrofuran. LCMS indicates liquid chromatography-mass spectrometry (¾ = retention time). Where ratios of solvents are given, the ratios are volume ratios.

Certain compounds of the examples and preparations were purified using automated high performance liquid chromatography (HPLC). Reversed phase HPLC conditions were with 25 FractionLynx systems. Samples were added dissolved in 1 ml of DMSO. Depending on the nature of the compounds and the results of a pre-analysis, the purification was carried out either under acidic conditions or under basic conditions at ambient temperature. Acid tests were performed with a Sunfaire Prep C18 OBD column (19 x 50 mm, 5 µm), basic tests were performed with a Xterra Prep MS C18 (19 x 50 mm, 5 μτη), both from Waters. A flow rate of 18 ml / min was used for the mobile phase A: water + 0.1% modifier (v / v) and B: acetonitrile + 0.1% modifier (v / v). For acid tests the modifier was formic acid, for basic tests the modifier was diethylamine. A Waters 39 2525 binary LC pump supplied a mobile phase with a composition of 55 B for 1 minute, then from 5% to 98% B in 6 minutes, followed by holding for 2 minutes at 98% B. Detection was performed using of a Waters 2487 dual wavelength absorption detector set at 225 nm, followed in series by a Polymer Labs PL-ELS 2100 detector and a parallel Waters ZQ 2000 4-way MUX mass spectrometer. The PL 2100 ELSD was set at 30 ° C with a supply of 1.6 1 / min nitrogen. The Waters ZQ MS was adjusted with the following parameters: ES + Cone voltage: 30 v Capillary: 3.20 kv ES- Cone voltage: -30 v Capillary: -3.00 kv 10 Desolvation gas: 600 1 / hour Source temp .: 120 ° C.

Scanning range 150-900 Da

Collecting the fraction was initiated by both MS and ELSD. Quality control analysis was performed using an LCMS-15 method orthogonal to the preparative method.

Acid tests were performed with a Sunfire Cl 8 (4.6 x 50 mm, 5 µm), basic tests were performed with a Xterra Cl 8 (4.6 x 50 mm, 5 µm), both from Waters. A flow rate of 1.5 ml / min was used for the mobile phase A: water + 0.1% modifier (v / v) and B: acetonitrile + 0.1% modifier (v / v). For acid tests the modifier was formic acid, for basic tests the modifier was diethylamine. A Waters 2525 binary LC pump performed a gradient elution from 5% to 95% B in 3 minutes, followed by holding at 95% B for 1 minute. Detection was performed using a Waters MUX UV 2488 detector set to 225 nm, followed in series by a Polymer Labs PL-ELS 2100 detector and a parallel Waters ZQ 2000 4-way MUX mass spectrometer. The PL 2100 ELSD was set at 30 ° C with a supply of 1.6 1 / min nitrogen. The Waters ZQ MS was adjusted with the following parameters: ES + Cone voltage: 25 v Capillary: 3.30 kv ES- Cone voltage: -30 v Capillary: -2.50 kv 30 Desolvation gas: 8001 / hour Source temp .: 150 ° C.

Scanning range 160-900 Da 40

Example 1 N-f6-amino-5- (2,3,5-trichlorophenyl) vrazine-2-yl-1-methyl-1H-pyrazole-5-carboxamide 5 (also known as 2-methyl-2H-pyrazole-3-) carboxylic acid r6-amino-5- (2,3,5-trichlorophenylpyrazine-2-yl) amide> 9 CH,

x L / irS

Λ01

Method A

N- (6-amino-5-chloropyrazin-2-yl) -1-methyl-1H-pyrazole-5-carboxamide (preparation 2, 0.05 g, 0.198 mmol) was combined with 2,3,5-trichlorobenzene boric acid (0.062 g, 0.28 mmol), cesium carbonate (0.045 g, 0.14 mmol) and palladium tetrakistriphenylphosphine (0.016 g, 0.014 mmol) and suspended in a mixture of 1,4-dioxane (5 ml) and water (1 ml ). The reaction was heated at 75 ° C for 5 hours and further amounts of cesium carbonate (0.04 g) and palladium tetrakistriphenylphosphine (0.01 g) were added. After an additional 1 hour at 75 ° C, the reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was dried (MgSO 4) and evaporated. The residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 1: 1 to give the product as an off-white solid (30 mg).

1 H NMR (de-DMSO): 4.09 (s, 3H), 6.13 (br s, 2H), 7.25 (d, 1H), 7.50-7.51 (m, 2H) , 7.90 (d, 1H), 8.55 (s, 1H), 10.60 (br s, 1H).

MS m / z 397 [MH] + 41

Example 2 N-r 6 -amino-S-f-2-Moron-5-methoxyphenyl-7-yl-2-yl-1-methyl-1H-pyrazole-5-carboxamide 5 CH, X

Method B

Oxalyl chloride (11.3 g, 89.5 mmol) was added to a suspension of 1-methyl-1 H-pyrazole-5-carboxylic acid (7.5 g, 59.5 mmol) in dichloromethane (100 ml). A drop of dimethylformamide was added and the reaction was allowed to stir for 7 hours at room temperature. An additional 7 ml of oxalyl chloride was added, followed by 1 drop of dimethylformamide and the reaction was stirred overnight at room temperature. The reaction was concentrated in vacuo and azeotroped with dichloromethane. The residue was dissolved in CH 3 CN (20 ml) and added to a solution of 3- (2-chloro-5-methoxyphenyl) pyrazme-2,6-diamine (preparation 6, 9.0 g, 35.9 mmol) and lutidine (5.2 ml, 46.7 mmol) in CH 3 CN (100 ml). The reaction was stirred at room temperature for 4 hours before being concentrated in vacuo. The residue was taken up in 200 ml of ethyl acetate and washed with 100 ml of water. The organic layer was collected and washed again with 50 ml of water and 50 ml of saline before drying over MgSC> 4 and concentrating in vacuo to give a sticky gum. The residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 2: 1 to give the product as a white solid.

1 H NMR (de-DMSO): 3.8 (3, s), 4.1 (3 H, s), 5.85 (2 H, br s), 6.95 (1 H, m), 7.05 (1 H, m), 7.25 (1 H, m), 7.45 (1 H, m), 7.5 (1 H, m), 8.55 (1 H, s).

42 LCMS Rt = 3.35 min MS m / z 359 [MH] +

EXAMPLE 3 N - [.alpha.-amino] - .beta. -7-chloro-2,3-dihydro-1,4-benzodioxin-5-van-pyrazine-2-vH-1-methyl-1H-pyrazole-5-carboxamide. (Λ nY ^ nh2

c, OT

10

Method C

Oxalyl chloride (36 μΐ, 0.41 mmol) was added to a suspension of 1-methyl-1 H-pyrazole-5-carboxylic acid (40 mg, 0.32 mmol) in dichloromethane (2 ml). A drop of dimethylformamide was added and the reaction was allowed to stir at room temperature for 3 hours before being concentrated in vacuo and azeotroped with dichloromethane. The resulting acid chloride was dissolved in 1 ml of anhydrous pyridine and added to a solution of 3- (7-chloro-2,3-dihydrobenzo [1,4] dioxin-5-yl) pyrazine-2,6-diamine (preparation 13, 50 mg, 0.18 mmol) in 2 ml of anhydrous pyridine. The reaction was heated to 60 ° C overnight before being concentrated in vacuo and partitioned between 5 ml of dichloromethane and 5 ml of water. The layers were separated using a phase separation sleeve and the organic layer was collected and concentrated in vacuo. The residue was dissolved in 1 ml of dimethyl sulfoxide and purified by preparative HPLC.

LCMS Rt - 3.14 min MS m / z 388 [MH] + 43

The following examples with the general formula: O CH.

rs nV-nh2

Ar 5 were prepared by methods analogous to methods A and B, as described for the foregoing, preparation details are as described for the method referred to.

Example No. Ar Name Data Preparation 4 2-chloro-5-fluorophenyl N- [6-amino-5- (2-chloro-5-LCMS) Rt = 2.92 min Method fluorophenyl) pyrazine-2-yl] -1- methyl MS m / z 347 [MH] + amino-5H-pyrazole-5-carboxamide-1H-pyra; 2) and 2-c 2,3-dichlorophenyl N- [6-amino-5- (2,3-MS m / z 363 [MH] + method dichlorophenyl) pyrazine-2-yl] -1- ^ -NMR (CDCl3): 4.25 amino-5-44 methyl-1H-pyrazole-5-carboxamide (s, 3H), 4.45 (br s, 2H), 1H-pyrazo 6.72 (s, 1H), 7.35 (m, 2) and 2H), 7.53 (s, 1H), 7.57 dichlorofei (m, 1H), 8.04 (br s, 1H), cesiumcarl 9.02 (s, 1H) . palladiumt 6 2,5-dichloro-3- N- [6-amino-5- (2,5-dichloro-3-MS m / z 393 [MH] + Method methoxyphenyl methoxyphenyl) pyrazine-2-yl] -1- 1 H-NMR (CDCl 3): 3.93 amino-5-cl methyl-1 H -pyrazole-5-carboxamide (s, 3 H), 4.22 (s, 3 H), 4.43 1 H-pyrazo (br s, 2H), 6.70 (s, 1H), 2), 2- 7.00 (s, 1H), 7.04 (s, 1H), 4.4.5.5-eth 7.50 (s, 1H), 7.98 (br s, (preparation 1H), 8.97 (s, 1H) cesiumcarl palladium t 7 2,5-dichlorophenyl N- [6-amino-5- (2,5-MS m / z) 363 [MH] + Method dichlorophenyl) pyrazine-2-yl] -1 H NMR (de-DMSO): amino-5-cl methyl-1H-pyrazole-5-carboxamide 4.10 (s, 3H), 6.00 (br s, 1H-pyrazo (also known as 2-methyl-2H-2H), 7.15 (s, 1H), 7.50-2) and 2.5-d pyrazole-3-carboxylic acid- [ 6-amino-5- 7.60 (m, 4H), 8.60 (s, (2,5-dichlorophenyl) pyrazin-2-yl] -1H), 10.60 (br s, 1H) amide) 45 8 2-chloro-3-N- [6-amino-5- (2-chloro-3-MS m / z 359 [MH] + Method methoxyphenyl methoxyphenyl) pyrazine-2-yl] -1- 1 H-NMR (CDCl3): 3.97 chloro-3-πκ methyl-1 H -pyrazole-5-carboxamide (s, 3 H), 4.26 (s, 3 H), 4.47 diamine (b <(br s, 2) H), 6.71 (s, 1H), lutidine and 7.03 (d, 2H), 7.37 (t, 1H), that is 7.53 (s, 1H), 7.99 (br s , carboxylic acid. 1 H), 9.01 (s, 1 H) 9 2,3-dichloro-6- N- [6-amino-5- (2,3-dichloro-6-MS m / z 394 [MH] + Method methoxyphenyl methoxyphenyl pyrazine-2-yl] -1 H-NMR (CDCl3): 3.76 (2,3-dichlocomethyl-1H-pyrazole-5-carboxamide (s, 3H), 4.25 (s, 3H) , 4.35 2,6-diamine (br s, 2 H), 6.71 (s, 1 H), equivalent 6.90 (d, 1 H), 7.52 (d, acid chloride 1 H), 8.01 (br s, 1H), 1H-pyrazoo 9.05 (s, 1H).

2-chloro-5- N- {6-amino-5- [2-chloro-5-LCMS Rt = 2.67 min Process (trifluoromethyl) phenyl (trifluoromethyl) phenyl] pyrazine-2-yl} - MS m / z 397 [MH] + amino-5-ch] 1-methyl-1H-pyrazole-5H-pyrazole-carboxamide 2) (trifluorometry at 80 ° C) 46 11 2-chloro-5-cyanophenyl N- [6-amino -5- (2-chloro-5-LCMS Rt = 2.31 min Process cyanophenyl) pyrazine-2-yl] -1-methyl-MS ES + 354 ES-352 amino-5-cl 1 H -pyrazole-5-carboxamide 1 H -pyrazoi 2) and 2 cl at 80 ° <47

Example 12 N- [6-amino-5- (2,3-dichloro-5-methoxyphenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-carboxamide 5.9 CH,

hn'M-n I IV

nV ^ nh; jTYci hsc, 0AV-c, N- (6-amino-5-chloropyrazin-2-yl) -1-methyl-1H-pyrazole-5-carboxamide (preparation 2, 0.1 g, 0.396 mmol) was combined with 2 - (2,3-dichloro-5-10 methoxyphenyl-4,4,5,5-tetramethyl- [1,2,2] dioxaborolane (preparation 18), (0.166 g, 0.515 mmol), cesium carbonate (0.129 g, 0.346 mmol) and palladium tetrakisphenylphosphine (0.046 g, 0.04 mmol) and suspended in a mixture of 1,4-dioxane (1 ml) and water (0.5 ml) The reaction was heated at 80 ° C for 5 hours. the reaction was cooled to room temperature and then concentrated in vacuo The residue was partitioned between an aqueous sodium carbonate solution (20 ml) and ethyl acetate (20 ml) and the organic layer was dried (Na 2 SC> 4) and concentrated in vacuo. residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 2: 3 to 1: 1 to give the product as an off-white solid (72 mg).

MS m / z 393 [MH] + 1 H NMR (CDCl 3): 3.80 (s, 3H), 4.23 (s, 3H), 4.43 (br s, 2H), 6.70 ( s, 1H), 6.90 (d, 1H), 7.10 (s, 1H), 7.50 (d, 1H), 8.05 (br s, 1H), 9.05 (s, 1H) .

48

The following examples with the general formula: O CH,

Au »ΝΥ ^ ΝΗ2

Ar 5 were prepared according to methods analogous to methods A and B, as described above, otherwise stated, preparation details are as described for the method referred to.

Example No. Ar Name Data Preparation 13 2,5-dichloro-3- N- [6-amino-5- (2,5-dichloro-3-LCMS) Rt = 1.62 min Method: methoxypheny methoxyphenyl) pyrazine-2- yl] -5-MS m / z 393 [MH] + (2,5-dich methylisoxazole-4-carboxamide 2,6-diamutidine) prepared carbonyl 49 14 2,3,5-trichlorophenyl N- [6-amino] 5- (2,3,5-MS m / z 398 [MH] + Process trichlorophenyl) pyrazine-2-yl] -5- (1 H-NMR (de-DMSO): amino-5-cl methylisoxazole-4-carboxamide (also 2.68 (s, 3H), 6.11 (br s, methyl isox known as 5-methyl isoxazole -4-2 H), 7.50 (d, 1 H), 7.89 (preparation of carboxylic acid [6-amino -5- (2,3,5- (d, 1H), 8.58 (s, 1H), trichlorophen trichlorophenyl) pyrazine-2-yl] amide) 9.19 (s, 1H), 10.60 (br s, 1 H).

2-chloro-5- N- [6-amino-5- (2-chloro-5-LCMS) Rt = 2.30 min Method methoxyphenyl methoxyphenyl) pyrazine-2-yl] -5-MS m / z 360 [MH ] + methylisox methylisoxazole-4-crboxamide chloro-5-diamine (e.g.

The following examples with the general formula: 9 CH3 tV-n Λ 0

NyV

Ar 50 were prepared according to methods analogous to methods A and C, as described above, otherwise stated are preparation details as described for the method referred to.

Example no. Ar Name Details Preparation? 16 2-chlorophenyl N- [6-amino-5- (2-MS m / z 330 [MH] + Process <chlorophenyl) pyrazin-2-yl] -3- [1 H-NMR (CDCl 3: 2.6 (s , amino-5-c methylisoxazole-4-carboxamide 3 H), 4.5 (br s, 2 H), 7.4 methyl iso (m, 3 H), 7.5 (m, 1 H), 7.9 (preparation ( br s, 1 H), 8.85 (s, 1 H), chlorophen 9.0 (s, 1 H).

Pd (PPh 3) 4 17 2,3-dichlorophenyl N- [6-amino-5- (2,3-MS m / z 364 [MH] + Method dichlorophenyl) pyrazine-2-yl] -3- ^ NMR ( CDCl3): 2.6 (s, amino-5-c methyl isoxazole-4-carboxamide 3 H), 4.5 (br s, 2 H), 7.35 methyl iso: (d, 2 H), 7.6 (m, 1 H ), 8.0 (preparation (br s, 1 H), 8.9 (s, 1 H), dichlorophen 9.0 (s, 1 H).

Pd (PPh3) 4 18 2,3,5-trichlorophenyl N- [6-amino-5- (2,3,5-MS m / z 398 [MH] + Method 51 trichlorophenyl) pyrazine-2-yl] -3 - 1 H-NMR (d 6 -DMSO): amino-5-chloc methylisoxazole-4-carboxamide also 2.42 (s, 3H), 6.15 (br s, methylisoxazc known as 3-methylisoxazole-2-4H), 7.50 (d, 1H), 7.91 (preparation of carboxylic acid [6-amino-5- (2,3,5- (d, 1H), 8,57 (s, 1H), trichlorophenyl trichlorophenyl) pyrazine -2-yl] -amide) 9.58 (s, 1H), 10.69 (br s, 1H).

19 1-Naphthyl N- [6-amino-5- (1-naphthyl) pyrazine-2-MS m / z 346 [MH] + Method A, yl] -3-methylisoxazole-4'-H-NMR (del DMSO): amino-5-chloc carboxamide (also known as 3- 2.50 (s, 3H), 5.70 (br s, methylisoxazc methylisoxazole-4-carboxylic acid (6-2H), 7.40-7, 60 (m, 5H), (preparation 3) (amino-5-naphthalene-1-ylpyrazine-2- 8.00 (m, 2H), 8.70 (s, yl) amide) 1H), 9.60 ( s, 1 H).

LCMS Rt = 2.86 min. 2,5-dichlorophenyl N- [6-amino-5- (2,5-MS m / z 366 [MH] + Method A, dichlorophenyl) pyrazine-2-yl] -3- 1 H-NMR (cU-DMSO): amino-5-chloc methylisoxazole-4-carboxamide (also 2.40 (s, 3H), 6.00 (br s, methylisoxazc known as 3-methylisoxazole-2-4H), 7.50-7.60 (m, 3H), (preparation of carboxylic acid [6-amino-5- (2.5-8.60 (s, 1H), 9.60 (s, 1H), dichlorophenyl dichlorophenyl) pyrazine-2-yl] -amide) 10.65 (br s, 1H).

21 7-chloro-2,3-dihydro-N- [6-amino-5- (7-chloro-2,3-dihydro-LCMS Rt = 3.21 min. Method C, 52 1,4-benzodioxin-5- yl 1,4-benzodioxin-5-yl) pyrazine-2 MS m / z 388 [MH] + chloro-2 yl] -3-methylisoxazol-4-yl] pyraz carboxamide and 3-methyl

The following examples with the general formula:

O

hn "^ r1

irS

ν-ννη2 were prepared by methods analogous to methods B and C, as described above using 3- (2,5-dichlorophenyl) pyrazine-2,6-diamine (preparation 11). Unless otherwise stated, the method of preparation referred to is.

10 53

Example ~ | no. R1 Name Data Bereidir 12 isoxazol-3-yl N- [6-amino-5- (2,5- ”LCMS Rt = 3.77 min. Work dichlorophenyl) pyrzine-2 MS m / z 350 [MH] + isoxazo <yl] isoxazole-3-carboxamide-lutidine "23 4-methyl-1,2,5- N- [6-amino-5- (2,5-MS m / z 363 [MH] + Werkwi oxadiazole-3 yl dichlorophenyl) pyrazine-2-yl] -4- 1 H NMR (CD 3 OD): 2.4 methyl-methyl-1,2,5-oxadiazole-3- (3H, s), 7.4-7.6 (3 H, m), Zuurchl crboxamide 8.75 (1 H, s) unresolved LCMS Rt - 2.56 min 24 5-methylisoxazole-4 N- [6-amino-5- (2,5-LCMS Rt = 2, 28 min. Actyl dichlorophenyl) pyrazine-2-yl] -5-MS m / z = 364 [MH] + methyl 11 methyl isoxazole-4-crboxamide.

1- (2-methoxyethyl) - N - [6-amino-5- (2,5-LCMS Rt = 2.82 min.) 1 H -pyrazol-5-yl dichlorophenyl) pyrazine-2-yl] -1- ( 2-MS m / z 407 [MH] + methox] methoxyethyl) -1H-pyrazole-5-carboxy carboxamide 26 isoxazolyl-4-yl N- [6-amino-5- (2,5-LCMS Rt = 2.80) min Werkwi dichlorophenyl) pyrazine-2 MS m / z 350 [MH] + isoxazolyl] isoxazole-4-carboxamide 54 27 1 - (2-methoxyethyl) - N- [6-amino-5- (2,5-LCMS) Rt = 2.83 min. Method 1H-pyrazol-3-yl dichlorophenyl) pyrazine-2-yl] -1- (2-MS m / z 407 [MH] + methoxy methoxyethyl) -1 H-pyrazole-3-carboxylic carboxamide

The following examples with the general formula:

O

were prepared according to methods analogous to methods B and C, as described above for the use of 3- (2-chloro-5-methoxyphenyl) pyrazine-2,6-diamine ( preparation 6). Unless otherwise stated, preparations have been made for the method referred to.

55

Example No. R1 Name Data Preparation 28 3-methylisoxazole-4- N- [6-amino * 5- (2-chloro-5-LCMS) Rt = 3.46 min Process yl methoxyphenyl) pyrazine-2-yl] -3- MS m / z 360 [MH] + equivalent methylisoxazole-4-carboxamide methyl-4-i; 29 4-methyl-1,2,5-N- [6-amino-5- (2-chloro-5-LCMS) Rt = 2.63 min Method oxadiazol-3-yl methoxyphenyl) pyrazine-2-yl] -4 - MS m / z 360 [MH] + methyl-1,2 methyl-1,2,5-oxadiazole-3-acid chloro carboxamide undiluted

Formation maintained with acid chloride becomes 4 da. 5-isopropylisoxazole-N- [6-amino-5- (2-chloro-5-LCMS Rt = 3.40 min. Method 4-yl methoxyphenyl) pyrazine-2-yl] -5-MS m / z 388 [MH] + isopropyl isopropylisoxazole-4-carboxamide Form Held 31 3-ethyl-5- N- [6-amino-5- (2-chloro-5-LCMS) Rt = 2.15 min Method methylisoxazole-4 -yl methoxyphenyl) pyrazine-2-yl] -3-MS m / z 388 [MH] + ethyl-5-methyl-5-methylisoxazole-4-acid chloro carboxamide thionyl chloride.

32 isoxazol-5-yl N- [6-amino-5- (2-chloro-5-LCMS Rt = 2.66 min. Method methoxyphenyl) pyrazme-2 MS m / z 346 [MH] + isoxazol-yl] isoxazole -5-carboxamide 33 isoxazol-4-yl N- [6-amino-5- (2-chloro-5-LCMS) Rt = 2.93 min Method <methoxyphenyl) pyrazine-2 MS m / z 345 [MH] + equivalent yljisoxazole-4-carboxamide 4-isoxazo (34 1- (2-methoxyethyl) - N- [6-amino-5- (2-chloro-5-LCMS) Rt = 2.98 min Method <1 H-pyrazole-5- yl methoxyphenyl) pyrazine-2-yl] -1- (2-MS m / z 402 [MH] + methoxyel methoxyethyl) -1H-pyrazole-5-carboxylic acid carboxamide 35- (2-methoxyethyl) - N- [6 -amino-5- (2-chloro-5-LCMS Rt = 2.63 min. Method <1 H -pyrazol-3-yl methoxyphenyl) pyrazine-2-yl] -1- (2-MS m / z 403 [MH] + methoxyel methoxyethyl) -1H-pyrazole-3-carboxylic acid carboxamide 36 3,5-N- [6-amino-5- (2-chloro-5-LCMS Rt = 4.3 min. Method <dimethylisoxazole-4-methoxyphenyl) pyrazine -2-yl] -3,5-MS m / z 374 [MH] + dimethylisyl dimethylisoxazole-4-carboxamide 57 37 isoxazol-3-yl N- [6-amino-5- (2-chloro-5-LCMS) Rt = 3.48 min. Method] methoxyphenyl) pyrazine-2-MS, m / z 346 [MH] + equivalent 'yl] isoxazole-3-carboxamide acid chloride isoxazolecar 38 5-propylisoxazole-4 N- [6-amino-5- (2-chloro-5-LCMS Rt) = 2.72 min Process] yl methoxyphenyl) pyrazine-2-yl] -5-MS m / z 386 [MH] + propyl-4-iso: propylisoxazole-4-carboxamide of the acid

The following examples with the general formula:

O

HN ^ R1

rS

Nvr 2 NH 2 joö 58 were prepared by methods analogous to methods B and C, as described above, using 3- (7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) pyrazine -2,6-diamine (preparation 13). Unless otherwise as described for the method referred to.

Example No. R1 Name Data Preparation 39 5-methylisoxazole-4- N- [6-amino-5- (7-chloro-2,3-dihydro-MS m / z 388 [MH] + Process yl 1,4-benzodioxin -5-yl) pyrazine-2- [NMR (cU-DMSO): equivalent yl] -5-methylisoxazole-4- 2.7 (3H, s), 4.25 (4H, m), acid chlorocarboxamide 5, 9 (2 H, br s), 6.85 (1 H, methyl isox s), 7.0 (1 H, s), 8.6 (1 H, s), 9.2 (1, s), 10.5 (1 H , br s).

LCMS Rt = 2.74 min 40 isoxazol-5-yl N- [6-amino-5- (7-chloro-2,3-dihydro-LCMS Rt = 2.82 min. Method 1,4-benzodioxin-5-yl pyrazine-2 MS m / z 374 [MH] + isoxazole; yl] isoxazole-5-carboxamide 41 4-methyl-1,2,5-N- [6-amino-5- (7-chloro-2,3-dihydro-LCMS) Rt = 3.10 min Method oxadiazole-3- yl 1,4-benzodioxin-5-yl) pyrazine-2-MS m / z 389 [MH] + methyl-1,2-yl] -4-methyl-1,2,5-oxadizole-3-acid chloro 59 carboxamide unsaturated 42 isoxazol-4-yl N- [6-amino-5- (7-chloro-2,3-dihydro-LCMS Rt = 3.11 min. Method; 1,4-benzodioxin-5-yl) pyrazine-2-MS m / z 374 [MH] + isoxazole and 1 µl of soxazole-4-carboxamide 43 isoxazol-3-yl N- [6-amino-5- (7-chloro-2,3-dihydro-LCMS Rt = 3.07 min. Method: 1,4-benzodioxin-5-yl) pyrazine-2-MS m / z 373 [MH] + isoxazolyl] isoxazole-3-carboxamide

The following examples with the general formula:

O

HN ^ R1

liS

60 were prepared by methods analogous to methods B and C, as described above, using 3- (1-naphthyl) pyrazine-2,6-diamine (preparation 8). Unless otherwise stated, preparation details 2 are referred to method.

Example No. R1 Name Data Preparation 44 4-methyl-1,2,5-N- [6-amino-5- (1-naphthyl) pyrazine-2-LCMS Rt = 2.76 min Process oxadiazol-3-yl yl ] -4-methyl-1,2,5-oxadiazole-3-MS m / z 346 [MH] + methyl-1,2-carboxamide Acid chloride undiluted Formation λ maintained 45 isoxazol-3-yl N- [6-amino-5 - (1-naphthyl) pyrazine-2-LCMS Rt = 3.65 min Process yl] isoxazole-3-carboxamide MS m / z 332 [MH] + isoxazole 46 1-methyl-1H- N- [6-amino-5 - (1-naphthyl) pyrazine-2 MS m / z 345 [MH] + Method

pyrazol-5-yl yl] -1-methyl-1 H -pyrazole-5'-H NMR (d ^ -DMSO): methyl-1H

carboxamide 4.1 (s, 3H), 5.7 (br s, 2H), 7.3 (m, 1H), 7.4-7.6 (m, SH), 8.0 (m, 2H) , 8.7 (s, 1H).

61 LCMS Rt = 2.72 min

The following examples with the general formula:

O

HN ^ R1

ifS

Ny ^ NH2 rrc '

Cl 3 were prepared by methods analogous to Method B, as previously described for pre-dichloro-3-methoxyphenyl) pyrazine-2,6-diamine (preparation 9). Unless otherwise stated, preparation details are as referred to.

10 62

Example No. R1 Name Data Preparation 47 4-methyl-1,2,5-N- [6-amino-5- (2,5-dichloro-3-LCMS Rt = 3.43 min. Method oxadiazol-3-yl methoxyphenyl pyrazine-2-yl] -4-MS m / z 394 [MH] + methyl-1,2-methyl-1,2,5-oxadiazole-3-acid chloro-carboxamide, undiluted

Formation retained 48 isoxazol-4-yl N- [6-amino-5- (2,5-dichloro-3-LCMS Rt = 3.11 min. Method methoxyphenyl) pyrazine-2 MS m / z 379 [MH] + isoxazole γ 1] isoxazole-4-carboxamide amide bin <63

Example 49 N- [6-amino-5- (2,5-dichloro-3-methoxyphenyl) pyrazine-2-yl] -3-methylisoxazole-4-carboxamide

TV, N

Λ 0 nV ^ nh2 iTc '

Cl 3

Oxalyl chloride (515 μΐ, 5.90 mmol) was added to a suspension of 3-methyl-4-isoxazole carboxylic acid (500 mg, 3.93 mmol) in dichloromethane (10 ml). A drop of dimethylformamide was added and the reaction was stirred at room temperature for 3 hours before being concentrated in vacuo and azeotroped with dichloromethane. The residue was dissolved in CH 3 CN (3.93 ml), whereby a 1 M solution was obtained. The 1 M solution of the resulting suction chloride (0.526 ml, 0.526 mmol) was added to a solution of 3- (2.5-15 dichloro-3-methoxyphenyl) pyrazine-2,6-diamme (preparation 9, 0.15 g , 0.526 mmol) and lutidine (89 μΐ, 0.787 mmol) in CH3 CN (10 ml). The reaction was stirred at room temperature for 4 days before being concentrated in vacuo. The residue was taken up in 10 ml of dichloromethane, washed with 5 ml of water and the two layers were separated using a phase separation sleeve. The organic layer was concentrated in vacuo to give a cream-colored solid. The residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 1: 1 to give 62 mg of the title product as a white solid / foam.

MS m / z 394 [MH] + 25 1 H NMR (de-DMSO): 2.4 (s, 3H), 3.9 (s, 3H), 6.0 (br s, 2H), 7.0 ( m, 1 H), 7.3 (m, 1 H), 8.6 (s, 1 H), 9.6 (s, 1 H), 10.65 (br s, 1 H).

LCMS Rt = 2.85 min 64

The following examples with the general formula:

O

HN ^ R1

rS

Uγ ^ ΝΗ2 ΝΗ were prepared by methods analogous to methods A and B, as described above, otherwise stated are preparation details as described for the method referred to.

Example No. R1 Name Data Preparation 50 5-methylisoxazole-4- N- [6-amino-5- (2-LCMS Rt = 3.00 min. Method chlorophenyl) pyrazine-2-yl] -5-MS m / z 330 [MH] + chlorofei methylisoxazole-4-carboxamide (prepared carbonyl 65 acid chloro 51 5-isopropylisoxazole-N- [6-amino-5- (2-LCMS Rt = 3.17 min. Method 4-yl chlorophenyl) pyrazine-2- yl] -5- MS m / z 358 [MH] + chloropheny isopropylisoxazole-4-carboxamide (preparation of carboxylate 52 isoxazol-3-yl N- [6-amino-5- (2-LCMS Rt = 2.96 min. Process chlorophenyl pyrazine-2-yl] isoxazole-MS m / z 316 [MH] + chloropheny-3-carboxamide (preparation

Formation sustained sustained 53 isoxazol-5-yl N- [6-amino-5- (2-LCMS Rt = 3.05 min. Process chlorophenyl) pyrazine-2-yl] isoxazole MS m / z 316 [MH] + chloropheny 5 -carboxamide (preparation of carbonic acid chloro *

Acylation 54 isoxazol-4-yl N- [6-amino-5- (2-LCMS Rt = 2.84 Process chlorophenyl) pyrazine-2-yl] isoxazole-MS m / z 316 [MH] + chloropheny-4-carboxamide ( preparation 66

Formation sustained 55 4-methyl-1,2,5-N- [6-amino-5- (2-LCMS Rt = 3.23 min. Method oxadiazol-3-yl chlorophenyl) pyrazine-2-yl] -4- methyl MS m / z 331 [MH] + chloropheny 1,2,5-oxadiazole-3-carboxamide (preparation oxadiazole prepared on thionylchlc 56 1- (2-methoxyethyl) - N- [6-amino-5- ( 2- LCMS Rt = 2.86 Process 1H-pyrazol-5-yl chlorophenyl) pyrazine-2-yl] -1- (2-MS m / z 373 [MH] + chloropheny methoxyethyl) -1H-pyrazole-5- ( preparation carboxamide pyrazole-5

Formation sustained 57 1-methyl-1H- N- [6-amino-5- (2-LCMS Rt = 2.75 min. Process pyrazol-5-yl chlorophenyl) pyrazine-2-yl] -1-methyl-MS m z 329 [MH] + amino-5-cl 1 H-pyrazole-5-carboxamide 1 H-pyrazol 2) and 2-chl 67

The following examples with the general formula:

O

HN ^ R1

rS

NspvNH 2 cc 5 were prepared by methods analogous to method B, as described above for example dichlorophenyl) pyrazine-2,6-diamine (preparation 7). Unless otherwise stated, preparation details are as referred to.

Example No. R1 Name Data Preparation 58 1- (2-methoxyethyl) - N- [6-amino-5- (2,3-LCMS Rt = 3.09 min. Method: 1H-pyrazol-5-yl dichlorophenyl) pyrazine- 2-yl] -1- (2-MS m / z 406 [MH] + methoxy methoxyethyl) -1H-pyrazole-5-carboxylic acid 68 carboxamide the amide 59 4-methyl-1,2,5-N- [6- amino-5- (2,3-LCMS Rt = 3.37 min. Method oxadiazol-3-yl dichlorophenyl) pyrazine-2-yl] -4-MS m / z 364 [MH] + methyl-1 methyl-1,2 5-oxadiazole-3-acid chloride carboxamide undiluted

Formation of 60 isoxazol-4-yl N- [6-amino-5- (2,3-LCMS Rt = 3.02 min. Method dichlorophenyl) pyrazine-2 MS m / z 349 [MH] + isoxazocyl] isoxazole- 4-carboxamide amide-bi 69

Example 61 N- [6-amino-5- (2,3,5-trichlorophenyl] pyrazine-2-yl-isoxazole-3-carboxamide

O

rV ° Λ [n 5 Cl- - ^ 'Cl N - [6-amino-5- (2,3,5-trichlorophenyl) pyizin-2-yl] isoxazole-3-carboxamide was prepared by a method analogous to method B, as described above for example 2, using 3-isoxazole carboxylic acid and 3- (2,3,5-10 trichlorophenyl) pyrazine-2,6-diamine (preparation 12).

LCMS Rt = 4.07 min. MS m / z 386 [MH] +

Example 62 N- (6-amino-5- (2,5-dichlorophenyl-pyrazine-2-yl) -1H-pyrazole-5-carboxamide

O

II H

N'n x iy fHf cr 70

Oxalyl chloride (0.17 ml, 1.9 mmol) was added to a suspension of 2- (2-trimethylsilanylmetlioxyethyl) -2H-pyrazole-3-carboxylic acid (Heterocycles (1992), 34, 303-314) (428 mg, 1 (76 mmol) in dichloromethane (15 ml), 1 drop of dimetfaylformamide was added and the reaction was stirred at room temperature under N 2 for 1 hour before being concentrated in vacuo and azeotroped with dichloromethane. The resulting acid chloride was dissolved in 5 ml of acetonitrile and added to a solution of 3- (2,5-dichlorophenyl) pyrazine-2,6-diamine (preparation 11, 300 mg, 1.18 mmol O in acetonitrile (15 ml) and 2 6-Lutidine (0.21 ml, 1.8 mmol) The reaction was stirred at room temperature under N 2 for 72 hours before being concentrated under vacuum and partitioned between 50 ml of ethyl acetate and 50 ml of water. MgSO 4 and concentrated in vacuo to give a brown oil that was purified by column chromatography (ethyl acetate, heptane, 1: 2) to give 52 mg of the title product.

15 'H NMR (CD3 OD) 0.00 (s, 9H), 1.90 (t, 2H), 3.65 (t, 2H), 5.55 (s, 2H), 6.95 (s, 1 H), 7.45-7.55 (m, 3 H), 7.90 (s, 1 H), 8.80 (s, 1 H).

To a suspension of the foregoing acylation product (10 mg, 0.21 mmol) in tetrahydrofnran (3 ml) was added tetrabutylammonium fluoride (0.022 ml, 0.0212 mmol, 1.0 M solution in tetrahydrofuran) and the reaction was run for 2 hours at 65 ° C 20 heated. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5 ml of ethyl acetate and 5 ml of water. The organic phase was dried over MgSO 4 and concentrated in vacuo. The resulting residue was dissolved in 1 ml of dimethyl sulfoxide and purified by preparative HPLC.

LCMS Rt = 2.04 min. 25 MS m / z 349 [MH] +

The following preparations illustrate the preparation of certain intermediates used to prepare the preceding examples.

Preparation 1 30 3-chloro-pyrazine-2,6-diamine 71 NH 2

rS

N> spVNH 2

Cl

Lithium hydroxide (12.4 g, 0.30 mol) was added to a cleaned suspension of 3,5-diamino-6-chloropyrazine-2-carboxylic acid methyl ester (20 g, 99 mmol) in methanol (300 ml) and water (120 ml) and the reaction was heated at 90 ° C for 1.5 hours before being allowed to cool to room temperature. The reaction was concentrated in vacuo to give a yellow suspension, and it was suspended in 1,4-dioxane (350 ml) and a 2 M aqueous HCl solution (200 ml) was added. The mixture was heated at 100 ° C for 2 hours and then allowed to cool before 1,4-dioxane was removed in vacuo. The resulting aqueous solution was adjusted to pH 8 with sodium carbonate (saturated aqueous) and extracted into ethyl acetate (3 x 300 ml). The combined organic layers were washed with brine (300 ml), dried (Na 2 SC> 4) and concentrated in vacuo to give a yellow solid (11.7 g, 82%).

1-NMR (de-DMSO): 5.95 (br s, 2H), 6.02 (br s, 2H), 6.82 (s, 1H).

MS m / z 147 [MH] +

Preparation 2 N- (6-amino-S-chloro-pyrazine-2-vl V1-methyl-1H-pyrazole-5-carboxamide O CH,

TAiiN

(i V

nY ^ nh2

Cl 25 72

Oxalyl chloride (0.288 ml, 3.32 mmol) was added to a suspension of 1-methyl-1H-pyrazole-5-carboxylic acid (0.299 g, 2.21 mmol) in dichloromethane (5 ml), followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before being concentrated in vacuo and azeotroped with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloropyrazine-2,6-diamine (preparation 1) (0.16 g, 1.11 mmol) and the mixture was kept at 60 ° C for 3 hours. heated before being cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 1: 1 to give the product as a light solid (100 mg).

1 H NMR (d 6 DMSO): 4.05 (s, 3H), 6.60 (br s, 2H), 7.20 (d, 1H), 7.50 (d, 1H), 8.30 (s, 1H), 10.60 (brs, 1H).

MS m / z 255 [MH] + 15

Preparation 3 N-f6-aminO'5-chloroDVTazine-2-vlV3-methylvisoxazole-4-carboxamide 9 CH3 rY ».

Λ 0

NyvNH 2 Cl

Oxalyl chloride (0.06 ml, 0.69 mmol) was added to a solution of 3-methylisoxazole-4-carboxylic acid (0.06 g, 0.48 mmol), followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before being concentrated in vacuo and azeotroped with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chlooipyrazine-2,6-diamine (preparation 1) (0.035 g, 0.24 mmol) in anhydrous pyridine (3 ml) and the mixture became 3 Heated at 50 ° C for 1 hour before being cooled to room temperature and concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 1: 1 to give the product as a white solid (30 mg).

5 '1 H NMR (de-DMSO): 2.40 (s, 3 H), 6.60 (br s, 2 H), 8.35 (s, 1 H), 9.60 (s, 1 Η), 10 65 (br s, 1H).

LCMS Rt = 2.35 min MS m / z 254 [MH] + 10 Preparation 4 N-r 6-amino-5-chloro-pyrazine-2-yl-V5-methylvisoxazole-4-carboxamide O CH, tYp o "

N'fV

Cl 15

Oxalyl chloride (0.8 ml, 10.3 mmol) was added to a solution of 5-methylisoxazole-4-carboxylic acid (1 g, 6.9 mmol) in dichloromethane (30 ml), followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 5 hours before being concentrated in vacuo and azeotroped with dichloromethane. The residue was taken up in pyridine (3 ml) and added to a solution of 3-chloropyrazine-2,6-diamine (preparation 1) (0.65 g, 4.6 mmol) in anhydrous pyridine (30 ml) and the mixture was heated at 50 ° C for 3 hours before being cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate: heptane 1: 1 to give the product as a white solid (360 mg).

^ -NMR (de-DMSO): 2.51 (s, 3H), 6.71 (br s, 2H), 8.35 (s, 1H), 9.12 (s, 1H), 10.63 ( br s, 1 H).

74 MS m / z 254 [MH] +

Preparation 5 5 3 - 5-di-amino-6- (2-chloro-5-methoxyphenyl) In vrazi-n-2-carboxylic acid methylene star O NH 2 Η3 ° ό \ ^ ν Ϊνη2

Cl

Method D

10

2-Chloro-5 was added to a suspension of 3,5-diamino-6-methylpyrazine-2-carboxylic acid methyl ester (10.9 g, 53.7 mmol) in 220 ml of 1,4-dioxane and water (40 ml). methoxybenzene boric acid (20 g, 107 mmol), cesium carbonate (17.5 g, 53.7 mmol) and palladium tetrakis (triphenyl phosphine) (620 mg, 0.54 mmol) added. The reaction was heated in an oil bath at 70-75 ° C for 2 hours. The reaction was then cooled and poured into 500 ml of water. The resulting suspension was stirred for 10 minutes before filtering under vacuum. The collected beige solid was then suspended in 100 ml of methanol, stirred for 15 minutes, then filtered, the filter cake was washed with methanol and dried under vacuum to yield 17.4 g of the title product.

1 H-NMR (d 1 -DMSO): 3.65 (s, 3H), 3.75 (s, 3H), 6.4 (br s, 2H), 6.9 (d, 1H), 7, 0 (dd, 1H), 7.05 (br s, 2H), 7.4 (d, 2H).

LCMS Rt = 3.74 min. MS m / z 309 [MH] + 25

Preparation 6 34'2-chloro-5-methoxyphenyl-pyrazine-2,6-diamine 75

NHL

Λ ιγ h3c.0A ^

Method E 5

To a suspension of 3,5-diamino-6- (2-chloro-5-methoxyphenyl) pyrazine-2-carboxylic acid methyl ester (preparation 5, 16.5 g, 53.4 mmol) in 255 ml of methanol and 76 ml of water LiOH (6.7 g, 160 mmol) was added and the reaction was stirred at 90 ° C for 2 hours. The reaction was concentrated to dryness under vacuum. The residue was suspended in 380 ml of 1,4-dioxane and 230 ml of 2 N HCl was added. The reaction was heated at 100 ° C for 1 hour before cooling to room temperature and concentrated in vacuo. The residue was made basic with 880 NH 3 and extracted into 2 x 300 ml of ethyl acetate. The organic layers were combined, dried with gSC> 4 and concentrated in vacuo. The solid residue was triturated with diethyl ether and filtered, yielding 10 g of a pale yellow solid.

1 H NMR (d * -DMSO): 3.25 (3H, s), 5.2 (br s, 2H), 5.9 (br s, 2H), 6.8 (d, 1H), 6 , 9 (dd, 1H), 7.15 (s, 1H), 7.4 (d, 1H).

LCMS Rt = 2.92 min. 20 MS m / z 251 [MH] +

Preparation 7 3- (2,3-dichlorophenyl-pyrazine-2-6-diamine 76 NH).

Λ νΥ ^ νη2 cc

Method F

Potassium cyanide (500 mg, 7.7 mmol) and 2-aminoacetamidine dihydrobromide ¢ 1.77 g, 7.5 mmol) were stirred in methanol (15 ml) for 1 hour at room temperature.

2,3-dichlorobenzaldehyde (1.34 g, 7.68 mmol) was added and the suspension was stirred overnight at room temperature. Lithium hydroxide monohydrate (1.0 g, 23.8 mmol) was added and the mixture was stirred at room temperature for 24 hours while open. The reaction mixture was partitioned between ethyl acetate (80 ml) and water (50 ml). The ethyl acetate solution was washed with water (30 ml), then dried over anhydrous sodium sulfate and evaporated in vacuo to give a light brown gum. This was purified by silica gel column chromatography eluting with ethyl acetate to yield 370 mg of the title product as a brown gum.

1 H NMR (CDCl3): 4.26 (br s, 2H), 4.43 (br s, 2H), 7.26 (d, 1H), 7.31 (m, 1H), 7.46 ( s, 1 H), 7.50 (d, 1 H) MS m / z 257 [MH] + 77

The following intermediates with the general formula: NH 2

(1 J

n ^ nh2

Ar 5 were prepared by a two-step process analogous to method D followed by we are preparation details as described above for the preparations 5 and 6.

Preparation no. Name Data Preparation information 8 3- (1-naphthyl) pyrazine-2,6-MS m / z 237 [MH] + Method D, diamine 1 H-NMR (de-DMSO): 5.1 (2, br s), 5.9 naphthalene boric acid.

(2 H, br s), 7.25 (1 H, s), 7.4-7.6 (5 H, m), Method E, under 7.9 (2 H, m). LiOH, HCl at 75 ° C for 2.5 h 9 3- (2,5-dichloro-3 MS m / z 285 [MH] + Method D, methoxyphenyl) pyrazine-2,6-1 H-NMR (CDCl 3): 3.95 (s, 3H), 4.35 (br 3-methoxyphenyl) -4.4 diamine s, 2H), 4.5 (br s, 2H), 6.95 (s, 1H) , 7.0 [1.3.2] dioxaborolar 78 (s, 1H), 7.5 (s, 1H). applying for 1 hour, given for 2 hours.

3- (2-chlorophenyl) pyrazine-2,6-MS m / z221 [MH] + Method D, o: diamine-NMR (d ^ -DMSO): 5.20 (br s, 2H), chlorophenylboric acid.

5.90 (br s, 2H), 7.15 (s, 1H), 7.30-7.40 (m, 3H), 7.45-7.50 (m, 1H) LCMS Rt = 2.01 min 11 3- (2,5-dichlorophenyl) pyrazine-MS m / z 255 [MH] + Method D, or 2,6-diamine 1 H-NMR (di-DMSO): 5.49 (2H, br s), dichlorophenyl boronum 6.03 (2H, br s), 7.15 (1H, s), 7.36 (1H, s), 7.42 (1H, d), 7.52 (1H, d) 12 3- (2 3,5-MS m / z 289 [MH] + Method D, under trichlorophenyl) pyrazine-2,6-1 H-NMR (CDCl3) 4.23 (2H, br s), 4.41 palladium tetrakis (trife diamine (2 H, br s), 7.35 (1 H, s), 7.50 (1 H, s) trichlorophenyl boron acid 13 3- (7-chloro-2,3-dihydro-1,4-MS m / z 279 [MH ] + Method D on benzodioxin-5-yl) pyrazine-1 H-NMR (CDCl 3): 4.28 (4H, m), 4.40 palladium tetrakis (trife 2,6-diamine (2H, br s), 4.46 (2H, br s), 6.91 (1H, s), dihydro-1,4-benzodio: 6.95 (1H, s), 7.47 23) 1.5 equivalent 1 ester hydrolysis (working 79

Preparation 14 3- (2,3-dichloro-6-methoxyphenylpyrazine-2,6-diamine NH.sub.2 NH.sub.2 NH.sub.3 -C.sub.3 O.sub.3 - (2,3-dichloro-6-methoxyphenyl) pyrazine-2,6-diamine was prepared according to a method analogous to method F as described above for preparation 7 and using 2,3-dichloro-6-methoxybenzaldehyde (preparation 27), the reaction was stirred with LiOH / air for 5 hours.

1 H NMR (CDCl3): 3.76 (s, 3H), 4.12 (br s, 2H), 4.35 (br s, 2H), 6.86 (d, 1H), 7.47 ( d, 1 H), 7.52 (s, 1 H) MS m / z 287 [MH] + 15 Preparation 15 3 - (2-chloro-3-methoxyphenyl-pyrazine-2,6-diamine NH,

rS

Nv, NH 2, RV 2 O 3 3- (2-chloro-3-methoxyphenyl) pyrazine-2,6-diamine was prepared by a method analogous to method F as previously described for preparation 7 and using 2- chloro-3-methoxybenzaldehyde.

80 1 H NMR (CD3 OD): 3.9 (3 H, s), 6.95 (1 H, m), 7.15 (1 H, m), 7.2 (1 H, s), 7.35 ( 1 H, m) MS m / z 251 [MH] +

Preparation 16 5 1-bromo-3-chloro-5-methoxybenzene H 3 Cl 2 XprBr

Cl 10 To a solution of 1-bromo-3-chloro-5-fluorobenzene (25 g, 0.12 mol) in methanol (800 ml) was added sodium methoxide (64 g, 1.18 mol), the reaction was 9 days cooked under reflux. The reaction was then concentrated in vacuo to one-fifth of the volume (150 ml), cooled and water (1000 ml) was added. The mixture was extracted with diethyl ether (3 x 150 ml). The organic layer was washed with brine (2 x 100 ml), dried (Na 2 SO 4) and evaporated to give the title product (24.6 g).

1 H NMR (CDCl 3): 3.80 (s, 3H), 6.84 (s, 1H), 6.96 (s, 1H), 7.10 (s, 1H).

GC-MS m / z 222 [MH] +, Rt - 3.86 min. Preparation 17 1-bromo-2,3-dichloro-5-methoxybenzene

", ^ I

Cl 1 -bromo-3-chloro-5-methoxybenzecn (preparation 16, 6.0 g, 27 mmol) and trichloroisocyanuric acid (2.3 g, 9.9 mmol) were dissolved in dimethyl formamide (100 mL) for 3 hours at 50 ° C stirred. N-heptane was added and the mixture was filtered to remove insoluble impurities. The mixture was then concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with n-heptane: ethyl acetate 9: 1 to give the title product as a white solid (5.0 g).

5 'H NMR (CDCl 3): 3.80 (s, 3H), 7.00 (s, 1H), 7.20 (s, 1H).

GC-MS m / z 256 [MH] +, R t = 4.60 min

Preparation 18 10 2-2,3-dichloro-5-methoxyphenyl-4A5,5-tetramethyl-1,3,21-dnxabnrolane

CH3 CH

VCH 3 H 3 Cl 2 .alpha

Cl 1-bromo-2,3-dichloro-5-methoxybenzene (preparation 17, 1.3 g, 5.1 mmol), bis (pinacolalo) dibor (1.4 g, 5.6 mmol), potassium acetate (1 , 5 g, 15 mmol) and Ι, Γ- [bis (diphenylphosphino) ferrocene] dichloro palladium (II) (0.37 g, 0.51 mmol) were combined and incubated for 5 hours at 83 ° C in a sealed vessel in dimethyl sulfoxide (10 ml) ). The mixture was then poured out on ice and extracted with diethyl ether. The organic layer was dried and evaporated. The residue was stirred in n-heptane, filtered and evaporated. This reaction was carried out three times and the crude material was pooled for purification by silica gel column chromatography eluting with n-heptane: ethyl acetate 9: 1 to give the product as a yellow oil (3.1 g).

1 H NMR (CDCl 3): 1.40 (s, 12H), 3.80 (s, 3H), 7.08 (s, 1H), 7.10 (s, 1H).

GC-MS m / z 304 [MH] +, Rt = 5.78 min

Preparation 19 1-bromo-2,5-dichloro-3-methoxybenzene 82 1-bromo-2,5-dichloro-3-fluorobenzene (40 g, 0.16 mol) and sodium methoxide 5 (44.3 g, 0.82 mol) were stirred for 16 hours at reflux temperature in methanol (500 ml). The reaction was cooled to ambient temperature and then quenched with water (500 ml). The mixture was extracted with diethyl ether (3 x 300 ml), dried (Na 2 SO 4) and evaporated to give the product as a white solid (40 g).

<1> H NMR (CDCl3): 3.90 (s, 3H), 6.86 (d, 1H), 7.26 (d, 1H).

MS m / z 256 [MHf GC-MS m / z 256 [MJ] +, Rt = 4.58 min

Preparation 20 2- (2,5-dichloro-3-methoxyphenyl-4,4,5,5-tetramethyl-1,3,21dioxahylan CH 2 H 2 F 3

V

jcx, ', cio 3 20 1-bromo-2,5-dichloro-3-methoxybenzene (preparation 19, 10 g, 39 mmol), bis (pinacolato) dibor (10.9 g, 43 mmol), potassium acetate (11 , 5 g, 117 mmol) and 1,1- [bis (diphenylphosphino) ferrocene] dichloro palladium (II) (2.8 g, 4.0 mmol) were combined and stirred in dimethyl sulfoxide (100 ml). The reaction flask was purged with nitrogen for 5 minutes before heating at 80 ° C for 16 hours. The mixture was cooled and dimethyl sulfoxide was removed in vacuo. The residue was partitioned between water (500 ml) and dichloromethane (3 x 200 ml). The organic layer 83 was washed with brine (300 ml), dried (Na 2 SO 4) and evaporated, yielding a black oil. The residue was dissolved in diethyl ether (200 ml) and filtered through a silica layer to give a green oil. This was purified using silica gel column chromatography 5, eluting with heptane: diethyl ether 7: 1 to give 5.6 g of the title product as a white solid.

1 H NMR (CDCl 3): 1.40 (s, 12H), 3.89 (s, 1H), 6.98 (s, 1H), 7.20 (s, 1H).

GC-MS m / z 304 [MH] +, Rt = 5.75 min. 10 Preparation 21 3-bromo-5-chlorobenzene-1,2-diol

To a stirred suspension of 3-bromo-5-chloro-2-hydroxybenzaldehyde (49.5 g, 0.21 mol) in 0.5 N aqueous NaOH (500 ml, 0.25 mol) was added at 40 ° C in 15 hydrogen peroxide (21.4 g of a 35% aqueous solution, 0.22 mol) was added dropwise for minutes and the resulting mixture was stirred for 16 hours. The mixture was cooled to room temperature, diluted with 1 N aqueous naOH (200 ml) and washed with diethyl ether (3 x 300 ml). The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with Et 2 O (3 x 200 mL). The organic extracts were combined, washed with brine, dried (Na 2 SO 4), filtered and concentrated in vacuo to give the desired product as a red-brown solid (46.0 g, 99%).

1 H NMR (CDCl 3): 5.40 (s, 1H), 5.55 (br s, 1H), 6.88 (d, 1H), 7.05 (d, 1H).

MS m / z 224 [MH] +

M.p. 71-73 ° C

30 Preparation 22 84 5-bromo-7-chloro-23-dihydrobenzof 1 -41dioxin

Jo 5 To a solution of 1,2-dibromoethane (1.44 ml, 16 mmol) and tetrabutylammonium bromide (96 mg, 2.5 mol%) in water (8 ml) was added a mixture of 3 under reflux under nitrogen in 4 hours bromo-5-chlorobenzene-1,2-diol (preparation 21, 2.68 g, 12 mmol) and naOH (1.06 g, 26.2 mmol) in water (10 mL) were added and the resulting mixture was added stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (100 ml). The mixture was extracted with Et 2 O (3 x 100 mL) and the combined organic extracts were concentrated in vacuo. Purification by evaporation chromatography (pentane: dichloromethane 9: 1) gave the desired product as a yellow oil (1.78 g, 60%), which crystallized on storage to a yellow solid.

15-NMR (CDCl 3): 4.27 (t, 2H), 4.35 (t, 2H), 6.86 (d, 1H), 7.10 (d, 1H).

M.p. 56.5-58.0 ° C

Preparation 23 20 (7-chloro-2,3-dihydro-1,4-benzodioxin-5-boric acid B (OH) 2 ο, Λ

To a stirred solution of 5-bromo-7-chloro-2,3-dihydrobenzo [1,4] dioxin 25 (preparation 22, 1.5 g, 6 mmol) in dry Et 2 O (45 ml) was added under nitrogen at -70 ° C n-butyllithium (2.63 ml of a 2.5 M solution in hexane, 6.6 mmol) was added and the resulting mixture was stirred for 1 hour. Trimethylborate (0.92 ml, 8 mmol) was then added and the mixture was stirred at room temperature overnight. Saturated aqueous NH 4 Cl was added (60 mL) and the aqueous layer was extracted with Et 2 O (3 x 100 mL). The combined organic extracts were concentrated in vacuo. The residue was taken up in 1 M aqueous NaOH and washed with Et 2 O (100 ml). The aqueous layer was then acidified with 2 N 5 aqueous HCl (pH 2) and extracted with diethyl ether (3 x 100 ml). The organic extracts were combined, dried (MgSO 4), filtered and concentrated in vacuo to give the desired product as a white solid (1.12 g, 87%).

1 H NMR (CDCl 3): 4.30 (t, 2H), 4.37 (t, 2H), 5.62 (2H, s), 6.99 (d, 1H), 7.37 (d, 1H).

M.p. 125-127 ° C

Preparation 24 2-bromo-4,6-dichlorophenol ir

To a solution of 2,4-dichlorophenol (4 g, 24.5 mmol) and sodium acetate (2 g, 24.5 mmol) in acetic acid (40 mL) was added bromine (1.3 mL, 24.5 mmol) and the reaction was stirred for 14 hours at room temperature. The reaction was poured into 600 ml of ice and filtered. The product was extracted in dichloromethane (200 ml), dried over sodium sulfate and concentrated in vacuo to give 5.5 g of the title product as a yellow solid.

"1 H NMR (CDCl 3): 5.02 (1H, s), 7.32 (1H, d), 7.42 (1H, d)

Preparation 25 1-bromo-3,5-dichloro-2-methoxybenzene 86

Br iV'CH '2-bromo-4,6-dichlorophenol (preparation 24, 4.6 g, 19 mmol), potassium carbonate (4.5 g, 32.3 mmol) and methyl iodide (1.8 ml, 20.5 mmol) were combined in 46 ml of acetone and refluxed for 18 hours. The reaction was cooled to 0 ° C, 1 N HCl (aqueous) was added to give pH 3 and the reaction was extracted in 50 ml of ethyl acetate. The organic layer was washed with brine (2 x 20 ml), dried over sodium sulfate and concentrated in vacuo to give the title compound as a brown solid (5.5 g).

1 H NMR (CDCl 3): 3.88 (3 H, s), 7.35 (1 H, m), 7.47 (1 H, m).

Preparation 26 2- (3,5-dichloro-2-methoxyphenyl-4,4,5,5-tetramethyl-1,3,21-dioxaborolane h3c CH3 h3c ^ ch3 ° 'B' ° jVch '1-bromo-3,5-dichloro-2- methoxybenzene (preparation 25, 4.4 g, 17.5 mmol) in 95 ml of diethyl ether was cooled to -78 ° C under nitrogen, tert-BuLi (10 ml, 35.16 mmol) was added dropwise and the reaction was Stirred for 15 minutes, 2-methoxy-4,4,5,5-tetramethyl-1,1,3,2-dioxaborolane (4.58 g, 29 mmol) was added and the reaction was stirred at -78 ° C for 1 hour. before the reaction was poured into 50 ml of ice-cold ammonium chloride (aqueous) .The product was extracted with diethyl ether (3 x 30 ml), the combined organic layers were washed with water 50 ml) and 87 saline (2 x 25 ml), dried over sodium sulfate and concentrated in vacuo to give a yellow oil. This was purified using silica gel column chromatography (heptane: ethyl acetate 9: 1), whereby a yellow oil, 4.5 g, was obtained.

5, 1 H-NMR (CDCl 3): 1.36 (12 H, s), 3.04 (3 H, s), 7.45 (1 H, d), 7.55 (1 H, d).

Preparation 27 2,3-dichloro-6-methoxybenzaldehyde 10 µg 3,4-dichloroanisole (12.5 g, 70.6 mmol) was dissolved in tetrahydrofuran (130 mL) and cooled to -76 ° C. n-butyl lithium (31 ml 2.5 molar in hexanes, 77.7 mmol) was added dropwise, keeping the temperature below -70 ° C. The solution was stirred at -70 ° C for 30 minutes and then dimethylformamide (6.0 ml, 77.7 mmol) was added dropwise. The mixture was allowed to warm to room temperature and then poured onto ice (500 ml) and extracted with diethyl ether. The ether extracts were washed with brine and then dried over anhydrous Na 2 SC> 4, filtered and the solvent removed in vacuo to give the crude product. This material was stirred and heated just under reflux temperature in hexane (100 ml) and dichloromethane (5 ml), then cooled and the solid was filtered off, whereby the title compound was obtained as an off-white powder (10.0 g).

1 H NMR (CDCl 3): 3.92 (s, 3H), 6.89 (d, 1H), 7.58 (d, 1H), 10.46 (s, 1H) MS m / z 206 [MH ] - CHN analysis: calculated, C, 46.86%, H, 2.95%, found, C, 47.01%, H, 3.01%, Preparation 28 88

Ethyl-1 - (2-methoxy-methyl-1H-pvrazole-3-carboxylate and Ethyl-1 - (2-methoxy-methyl-1H-pyrazole-5-caTboxylate)

Vy "- Vvs

r ° ^ r ° S

HX I HX CHo 3 3 3

s V

2-methoxyethyl hydrazine hydrochloride (see: J. Med. Chem. (1967) 11 (1) 79-83) (1.07 g, 8.5 mmol) and ethyl 4-dimethylamino-2-oxobut-3-enoate (1.5 g, 8.5 mmol) were dissolved in ethanol (10 mL) and heated at 60 ° C for 7 hours. The solution was evaporated in vacuo and the residue was partitioned between ethyl acetate (80 ml) and a dilute sodium carbonate solution (40 ml). The organic layer was dried over anhydrous Na 2 SC> 4 and the solvent was removed in vacuo to give a brown gum. This material was chromatographed on silica gel (30 g) using 40% to 20% heptane in ethyl acetate. The higher-running product was collected, whereby 2- (2-methoxyethyl) -2H-pyrazole-3-carboxylic acid ethyl ester was obtained as 750 mg of a mobile yellow oil. The lower running product was collected, yielding 1- (2-methoxyethyl) -1 H -pyrazole-3-carboxylic acid ethyl ester as 360 mg of a yellow oil.

Data for 1- (2-methoxyethyl) -1 H -pyrazole-5-carboxylic acid: 20 1 H NMR (CDCl 3): 1.37 (t, 3H), 3.32 (s, 3H), 3.77 (t (2H), 4.34 (q, 2H), 4.77 (t, 2H), 6.84 (s, 1H), 7.50 (s, 1H) MS m / z 199 [MH] +

The structures were confirmed by gHMBC (Heteronuclear Multiple Binding Correlation) and gHSQC (Homonuclear Single Quantum Coherence) NMR-25 techniques.

Data for 1- (2-methoxyethyl) -1 H -pyrazole-3-carboxylic acid: 1 H NMR (CDCl 3): 1.32 (t, 3H), 3.25 (s, 3H), 3.68 (t, 2H), 4.29 (t, 2H), 4.33 (q, 2H), 6.72 (s, 1H), 7.44 (s, 1H) MS m / z 199 [MH] + 89

Preparation 29 1 -f2-methoxyethyl-1H-pvrazole-5-carboxylic acid 5

VvN

HO

/O

h3c

Ethyl 1- (2-methoxyethyl) -1 H -pyrazole-5-carboxylate (preparation 28, 710 mg, 3.6 mmol) was dissolved in ethanol (10 mL), a solution of sodium hydroxide 10 (160 mg, 4 (0 mmol) in water (5 ml) was added and the solution was stirred at room temperature for 2 hours. The ethanol was removed in vacuo and the residue was acidified with 2 M HCl (about 2 mL) and extracted with dichloromethane (40 mL). The organic layers were dried over anhydrous Na 2 SO 4, filtered and the dichloromethane was removed in vacuo to give 590 mg of a light yellow foam.

1 H NMR (CDCl 3): 3.28 (s, 3H), 3.75 (t, 2H), 4.73 (t, 2H), 6.91 (d, 1H), 7.51 (d, 1 H) MS m / z 171 [MH] +

Preparation 30 1- (2-methoxyethyl-1H-pyrazole-3-carboxylic acid

VvS

HO

\ ch3 90

Ethyl 1 - (2-methoxyethyl) -1 H -pyrazole-3-carboxylate (preparation 28, 360 mg, 1.8 mmol) was dissolved in ethanol (6 ml), a solution of sodium hydroxide (90 mg, 2) (3 mmol) in water (3 ml) was added and the solution was stirred at room temperature for 3 hours. The ethanol was removed in vacuo and the residue was acidified with 2 M HCl (about 1.5 ml), the aqueous solution was evaporated to dryness in vacuo and the residue was extracted with a mixture of dichloromethane (15 ml) and 3 drops methanol. The mixture was filtered to remove the inorganic materials and the solvent was removed in vacuo to yield 310 mg of a yellow oil that crystallized on storage.

^ -NMR (CDCl 3): 3.33 (s, 3H), 3.78 (t, 2H), 4.40 (t, 2H), 6.86 (d, 1H), 7.54 (d, 1H) ) MS m / z 171 [MHf

The ability of the pyrazine derivatives of formula (I) to inhibit the Navi g channel can be measured using the assay described below.

VIPR assav for Nav1,8 compounds This assay is used to determine the effects of compounds on tetrodotoxin resistant (TTX-R) sodium channels in the Human Navl.8 (HEK293) expressing cell line, using the technology from Aurora's fluorescent Voltage / Ion-Probe Reader (VIPR). This experiment is based on FRET (Fluorescent Resonance Energy Transfer) and two fluorescent molecules are used. The first molecule, Oxonol (DiSBAC2 (3)), is a highly fluorescent, negatively charged, hydrophobic ion that "senses" the trans-membrane electric potential. In response to changes in the membrane potential, it can quickly redistribute between two binding sites on opposite sides of the plasma membrane. The voltage-dependent redistribution is converted into a ratiometric fluorescence reading via a second fluorescent molecule (coumarin (CC2-DMPE)) which specifically binds to a surface of the plasma membrane and acts as a FRET partner for the mobile voltage sensing ion. To allow the assay to work, 91 channels must be kept pharmacologically in the open state. This is achieved by treating the cells with either deltametrien (for Navis) or veratridine (for the SHS Y-5 Y assay for TTX-S channels).

Cell Maintenance: 5 Navl.8 human cells are grown in T225 flasks, in a 5% CO 2 humidified incubator, to approximately 70% confluence. The composition of the medium consists of DMEM / F-12, 10% FCS and 300 pg / ml Geneticin. They are cleaved using cell dissociation fluid 1: 5 to 1:20 depending on schematic needs, and cultured for 3-4 days for the next cleavage.

10 Protocol:

Day one:

Plate HEK-Navl.8 cells (100 μΐ per well) for the experiment onto poly-D-lysine coated plates as follows: - 24 hours @ 3.5 x 104 cells / well (3.5 x 105 cells / ml) or using the technology of Kiezen.

Day two: VIPR assay: 1. Equilibrate buffers for 2 hours at room temperature or 30 minutes at 37 ° C for the experiment.

2. Prepare coumarin dye (see below) and store in the dark. Prepare with the plate detergent with Na + free buffer and wash the cells twice, note: plate detergent deposits ~ 30 μΐ remaining buffer per well. Add 100 μΐ coumarin (CC2-DMPE) solution (see below) to the cells and incubate for 45 minutes at room temperature while avoiding bright light.

3. Prepare oxonol (DiSBAC2 (3)) dye (see below): 4. Aspirate the coumarin solution from the cells by washing in Na + free buffer.

5. Add 30 μΐ of compound, then add 30 μΐ of oxonol solution to the cells and incubate for 45 minutes at room temperature in the dark (total volume of the well ~ 90 μΐ).

6. Once the incubation is complete, the cells are ready to be tested for sodium addback membrane potential using VIPR.

The data was analyzed and reported as normalized ratios of intensities measured in the 460 nm and 580 nm channels. The method of calculating these ratios was performed as follows. An additional plate 92 contained control solution with the same DisBAC2 (3) concentrations as were used with the cell plates, however, no cells were included in the background plate. Intensity values at each wavelength were averaged for montser points 5-7 (initial) and 44-49 (final). These averages were subtracted from the intensity values that were averaged over the same time periods for all assay wells. The initial ratio obtained with samples 3-8 (R1) and the final ratio obtained with samples 45-50 (Rf) is defined as: 10 Ri = (Intensity 460 nm, samples 3-5 - background 460 nm, samples 3-51 (Intensity 580 nm, samples 3-5 - background 580 nm, samples 3-5)

Rf = (Intensity 460 nm. Samples 25-30 - background 460 nm. Samples 25-301 (Intensity 580 nm, Samples 25-30 - Background 580 nm, Samples 25-30) 15

The final data is normalized with respect to the starting ratio of each well and reported as Rf / Ri. This analysis is performed using an automated specific program designed for data generated by VIPR. RiTRi ratio values are plotted using Excel Labstats (curve adjustment) or analyzed via ECADA to determine an IC50 value for each connection.

Na + -Addback buffer pH 7.4 (adjusted with 5 M NaOH) - 10X stock

Component: Mwt / Conc ”: a weight / volume lOXConc. (mM) IX Conc. (mM):

NaCl 58.44 93.5 g 1600 160 KCl 74.55 3.35 g 45.0 4.5

CaCl 2 1M solution 20 ml 20.0 2

MgCl 2 203.31 2.03 g 10.0 1

Hepes 238.3 23.83 g 100 10 dH 2 O 11 93

Na + free buffer pH 7.4 (adjusted with 5 Μ KOH) - 10X stock

Component: Mwt / Conc ”: weight / volume IPX Cone. (mM) IX Conc. (mM):

Choline 139.6 223.36 g 1600 160

CaCl 2 1M solution 1 ml 1.0 0.1

MgCl 2 203.31 2.03 g 10.0 1.0

Hepes 238.3 23.83 g 100 10 dH 2 O 1 I 1 Na + free buffer: - 400 ml 10X + 3600 ml dH20 2X Na + free buffer: -100 ml 10X + 400 ml dH 2 O 5 IX Na + - Addback buffer: - 50 ml 10X Na + -Addback + 450 ml dH20 coumarin (CC2-DMPE): for 2 plates: - 10 First mix 220 μΐ coumarin (1 mM) + 22 μΐ Pluronic (20%) in a tube + 22 ml IX Na + free buffer, gently shake.

Solution Conc ": Ultimate assav-conc"

Coumarin (1 mM) 10 μΜ 10 μΜ 15

Oxonol (DiSBAC2 (3)): for 2 plates: - 48 μΐ oxonol (5 mM) +120 μΐ tartrazine (200 mM) shake 8.0 ml 2X Na + free buffer shake 20 1.6 μΐ deltaametherine (5 mM) shake 94

Solution Cone ": final assav-conc11

Oxonol (5 mM) 30 μΜ 10 μΜ

Delta amine (5 mM) 1 μΜ 330 nM

Tartrazine (200 mM) 3 mM 1.0 mM

TTX-S assay

The TTX-S assay is performed in the SHSY-5Y cell line which constitutively expresses a number of tetrodotoxin sensitive, stress-directed sodium channels, including Navi.2, Navu and Navi.7. The method detailed above for the Navi.g assay was followed, with the exception that veratridine was substituted for deltamethrin in the assay as an opener of the sodium channels, in a final assay concentration of 50 μΜ.

Compounds of the examples were tested in the assay described above, using an automated dissolution method to obtain a solution of the test compounds.

Example No. Nayi.e IC50 (μΜ) TTX-S IC50 (μΜ) Selectivity ratio ~ 2 3 ^ 24 38] 3 TÜ8 “3 15 ^ 2> 28.8> 1.89 1 8/73> 30.2> 3 46 _ _ -> 26.3 -> 4.28 ~ 6 4 / Π> 20.0> 4.25 T 3,8 3.80 20 ^ 5 5 ^ 40 T M M7> 30.2> 6.76 ~ Y2 16ï 16 ^ 6 12 ^ 67 "33 ÏÖ ^ 4> 25.8> 2.48 TT ÏJé 14J 3Ö3 15> 30.2> 30.4 - TT Π0Ϊ> 24.0> 23.6 95 ~ Ï7 0.425 12, 5 29.4 0.511 9 ^ 20 18.00 "~ 21 ^ 81 20 ^ 9 4 ^ 5 ^ 3 8 ^ 04> 28.5> 3.54 ^ 28 ~ 2jb \ 25 ^ 6 9 £ ^ 9 7 ^ 7> 29.4> 3.69 ~ 3 0 "3 ^ 63> 29.6> 8.15 ~ 3 5/38> 28.1> 5.22 ~ 32 6 ^ 12> 30.2> 4.93 ~ 33> 22.7 -> 30.2 -> 1.33 ~ 34 15 ^ 6 -> 30.2 -> 1.94 36 13 ^ 9> 30.2> 2.18 ~ 37> 29.4> 30 , 2 -

"38> 30.2> 30.4 L

~ 39 "5A5> 17.7 ~> 305 ~ 4I 12/7> 28.2> 2.22 ~ 43> 21.1> 20.1 -> 1.43" 44 I3> 27.4> 1 ^ 7 ~ 48 8 ^ 06> 30.2> 3.75 ~ 49 0.629> 13.6> 21.6 ~ 5Ö ÏÖ / 3> 29.9> 2.90 "" 5Ï 0.964> 21.1> 21.89 ~ 55> 21.5 -> 30.2 -> 1.40 56> 26.7> 30/2 -

"57> 28 ^ 4> 30.2 I

58 42 42> 30.2 "> 3 ^ ~ 59 7 ^ 23> 25.9> 3.58« V9> 30.2> 4.20

~ 62 ~> 3 (Ü> 30.2 l

Where experiments were performed in duplicate resulting in multiple sets of data for a test compound, the data displayed represents the average value of all experiments in duplicate.

96

Certain compounds of the examples were also tested in the assay described above in which a manual dissolution method was followed to obtain a solution of the test compounds. Data thus obtained is shown below:

Example No. Navi s IC50 (μΜ) TTX-S IC50 (μΜ) Selectivity ratio

1 0,988

14 0.276 3A9 12J

18 0.417> 30.0> 72.0 ~ 7 3 ^ 98 Ϊ5Λ 3/79 19 4/72> 30.0> 6.36 "2Ö 0.188 123 663

Where experiments were performed in duplicate resulting in multiple sets of data for a test compound, the data displayed represents the average value of all experiments in duplicate.

2 o 0 £ 8 *

Claims (16)

A compound of the formula (I): O X A "" γΑ A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein Ar 25 is 2 000284 κΜγ01. 5 A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 or claim 2, wherein each R 2 is independently selected from hydrogen, methoxy, ethoxy, cyano, methyl, ethyl, trifluoromethyl, trifluoromethoxy, chlorine and fluorine. 10 A compound of formula (I), or a pharmaceutically acceptable salt or A solvate thereof, according to any of claims 1 to 3, wherein each R is independently selected from hydrogen, methoxy, cyano, trifluoromethyl, chlorine and fluorine. 15 A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 4, wherein Ar 2-chlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 2, 5-dichloro-3-methoxyphenyl, 2,3,5-trichlorophenyl, 2-chloro-5-methoxyphenyl, 2,3-dichloro-5-methoxyphenyl or 2-chloro-5-cyanophenyl. 20 Ar or a pharmaceutically acceptable salt or solvate thereof; wherein R 1 is a 5 membered heteroaryl group comprising either (a) 1 to 4 nitrogen atoms or (b) a acid or a sulfur atom and 0, 1 or 2 nitrogen atoms, optionally substituted with one or more subsituents each independently selected from (C 1 -C 4) alkyl, (C 1 -C 4 alkoxy, halogen (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy (C 1 -C 4 alkyl, amino (C 1 -C 4) alkyl, amino, (C 1 -C 4) alkylamino , di ((C 1 -C 4) alkyl) amino, (C 1 -C 4) alkylamino (C 1 -C 4) alkyl and di ((C 1 -C 4) alkyl) amino (C 1 -C 4) alkyl, provided that R 1 is not imidazolyl , oxazolyl or 1,2,4-triazolyl; A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 5, wherein R 1 is pyrazolyl or isoxazolyl, each optionally substituted with (C 1 -C 4 alkyl or ( C 1 -C 4 alkoxy (C 1 -C 4) alkyl A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 6, wherein R 1 is pyrazolyl or isoxazolyl, each of which is substituted with one, two or three substituents that become independent selected from methyl, ethyl and isopropyl. 30 A compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any of claims 1 to 7, wherein R 1 is 3-methylisoxazol-4-yl, 1-methyl-1H-pyrazol-5-yl 5-isopropylisoxazol-4-yl, 5-methylisoxazol-4-yl or 3-ethyl-5-methylisoxazol-4-yl. 5 A compound of the formula (I) according to any of claims 1 to 8, selected from: N- [6-amino-5- (2,3-dichlorophenyl) pyrazin-2-yl] -3-methylisoxazole-4 -carboxamide; N- [6-amino-5- (2,5-dichlorophenyl) pyrazin-2-yl] -3-methylisoxazole-4-carboxamide; A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 9, together with one or more pharmaceutically acceptable excipients. N- [6-amino-5- (2,5-dichloro-3-methoxyphenyl) pyrazine-2-yl] -3-methylisoxazole-4-carboxamide; N- [6-amino * 5- (2,3-dichloro-5-methoxyphenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-carboxamide; N- [6-amino-5- (2-chlorophenyl) pyrazin-2-yl] -5-isopropylisoxazole-4-caiboxamide; A compound with the fomral (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 9, for use as a medicament. The use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 10 with 9, for the preparation of a medicament for the treatment of a disease or condition wherein a Navj8 channel modulator is indicated. The use of claim 12, wherein the disease or condition is pain. A compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 9, for use in the treatment of a disease or condition in which a NaVi8 channel modulator is indicated. A compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 9, for use in the treatment of pain. N- [6-amino-5- (2-chlorophenyl) pyrazin-2-yl] -3-methylisoxazole-4-carboxamide; N- [6-amino-5- (2,3,5-trichlorophenyl) pyrazin-2-yl] -5-methylisoxazole-4-carboxamide; N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazine-2-yl] -3-methylisoxazole-4-carboxamide; N- [6-amino-5- (2-chloro-5-cyanophenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-20 carboxamide; N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazine-2-yl] -3-ethyl-5-methylisoxazole-4-carboxamide; N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazine-2-yl] -1-methyl-1H-pyrazole-5-carboxamide; N- [6-amino-5- {2,5-dichlorophenyl) pyrazin-2-yl] -1-methyl-1H-pyrazole-5-carboxamide; and N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyrazin-2-yl] -5-isopropylisoxazole-4-carboxamide; or a pharmaceutically acceptable salt or solvate thereof. 30 15 Ar Λ * Λ), and represents the point of attachment to the pyrazine ring and each R 2 is independently selected from hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, halogen (C 1 -C 4) alkyl, halogen (C 1 -C 4) alkoxy, cyano and halogen. A combination of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 9, and another pharmacologically active agent. xxxxx 2 00 02 84